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Publication numberUS7754723 B2
Publication typeGrant
Application numberUS 11/478,462
Publication dateJul 13, 2010
Filing dateJun 28, 2006
Priority dateDec 30, 2003
Fee statusPaid
Also published asCA2551862A1, CN1902178A, DE602004019576D1, EP1727801A1, EP1727801B1, US20070032500, WO2005066130A1
Publication number11478462, 478462, US 7754723 B2, US 7754723B2, US-B2-7754723, US7754723 B2, US7754723B2
InventorsQun Sun, Laykea Tafesse
Original AssigneePurdue Pharma, L.P., Usa
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Therapeutic agents useful for treating pain
US 7754723 B2
Abstract
Compounds of formulae:

where Ar1, Ar2, R3, R4, and m are disclosed herein, or a pharmaceutically acceptable salt thereof (a “Nitro(cyano)vinylpiperazine Compound”); compositions comprising an effective amount of a Nitro(cyano)vinylpiperazine Compound; and methods for treating or preventing pain and other conditions in an animal comprising administering to an animal in need thereof an effective amount of a Nitro(cyano)vinylpiperazine Compound are disclosed.
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Claims(70)
1. A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein
Ar1 is
Ar2 is
R1 is —H, -halo, —CH3, —CN, —NO2, —OCH3, —NH2, —C(halo)3, —CH(halo)2, or —CH2(halo);
each R2 is independently:
(a) -halo, —OH, —NH2, —CN, or —NO2;
(b) —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C8)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
each R3 is independently:
(a) -halo, —OH, —NH2, —CN, or —NO2;
(b) —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
R4 is —H, —CN, —C(O)O(C1-C4)alkyl, or —C(O)NH((C1-C4)alkyl);
each R5 is independently —CN, —OH, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6) alkynyl, -halo, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;
each R6 is independently —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, -halo, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;
each R7 is independently —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)3, —CH(halo)2, or —CH2(halo);
each R8 is independently —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, —halo, —N3, —NO2, —N(R7)2, —CH═NR2, —NR7OH, —OR2, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;
each halo is independently —F, —Cl, —Br, or —I;
m is an integer ranging from 0 to 2;
n is an integer ranging from 0 to 3;
q is an integer ranging from 0 to 6;
r is an integer ranging from 0 to 5; and
s is an integer ranging from 0 to 4.
2. The compound of claim 1, wherein R4 is —CN, —C(O)O(C1-C4)alkyl, or —C(O)NH((C1-C4)alkyl).
3. The compound of claim 1, wherein R4 is —H.
4. The compound of claim 3, wherein:
R1 is -halo, —C(halo)3, or —CH3;
n is 0;
m is 0; and
Ar2 is
5. The compound of claim 4, wherein r is 0, 1 or 2 and when r is 1 or 2 Ar2 is substituted at its para-position with an R8 group.
6. The compound of claim 3, wherein:
R1 is -halo, —C(halo)3, or —CH3;
n is 0;
m is 1;
R3 is methyl; and
Ar2 is
7. The compound of claim 6, wherein r is 0, 1 or 2 and when r is 1 or 2 Ar2 is substituted at its para-position with an R8 group.
8. A compound of formula (II):
or a pharmaceutically acceptable salt thereof, wherein
Ar1 is
Ar2 is
R1 is —H, -halo, —CH3, —CN, —NO2, —OCH3, —NH2, —C(halo)3, —CH(halo)2, or —CH2(halo);
each R2 is independently:
(a) -halo, —OH, —NH2, —CN, or —NO2;
(b) —(C1 -C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C8)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
each R3 is independently:
(a) -halo, —OH, —NH2, —CN, or —NO2;
(b) —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
R4 is —H, —CN, —C(O)O(C1-C4)alkyl, or —C(O)NH((C1-C4)alkyl);
each R5 is independently —CN, —OH, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, -halo, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;
each R6 is independently —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, -halo, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;
each R7 is independently —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)3, —CH(halo)2, or —CH2(halo);
each R8 is independently —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, -(3- to 7-membered)heterocycle, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, -halo, —N3, —NO2, —N(R7)2, —CH═NR2, —NR7OH, —OR2, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;
each halo is independently —F, —Cl, —Br, or —I;
m is an integer ranging from 0 to 2;
n is an integer ranging from 0 to 3;
q is an integer ranging from 0 to 6;
r is an integer ranging from 0 to 5; and
s is an integer ranging from 0 to 4.
9. The compound of claim 8, wherein R4 is —CN, —C(O)O(C1-C4)alkyl, or —C(O)NH((C1-C4)alkyl).
10. The compound of claim 8, wherein R4 is —H.
11. The compound of claim 10, wherein:
R1 is -halo, —C(halo)3, or —CH3;
n is 0;
m is 0; and
Ar2 is
12. The compound of claim 11, wherein r is 0, 1 or 2 and when r is 1 or 2 Ar2 is substituted at its para-position with an R8 group.
13. The compound of claim 10, wherein:
R1 is -halo, —C(halo)3, or —CH3;
n is 0;
m is 1;
R3 is methyl; and
Ar2, is
14. The compound of claim 13, wherein r is 0, 1 or 2 and when r is 1 or 2 Ar2 is substituted at its para-position with an R8 group.
15. A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1, and a pharmaceutically acceptable vehicle.
16. A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 8, and a pharmaceutically acceptable vehicle.
17. An in vivo method for inhibiting VR1 function in a cell, comprising contacting a cell capable of expressing VR1 in vivo with an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1.
18. An in vivo method for inhibiting VR1 function in a cell, comprising contacting a cell capable of expressing VR1 in vivo with an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 8.
19. The compound of claim 4, wherein R1 is —F, —Cl, —CF3 or —CH3.
20. The compound of claim 5, wherein each R8 is independently selected from -halo, -cyclohexyl, -tert-butoxy, -iso-propoxy, —CF3, —OCF3, or —(C1-C6)alkyl, wherein optionally each R8 —(C1-C6)alkyl is independently selected from -iso-propyl, -tert-butyl, -iso-butyl or -sec-butyl.
21. The compound of claim 6, wherein R1 is —F, —Cl, —CF3 or —CH3.
22. The compound of claim 7, wherein each R8 is independently selected from -halo, -cyclohexyl, -tert-butoxy, -iso-propoxy, -CF3, —OCF3, or —(C1-C6)alkyl, wherein optionally each R8 —(C1-C6)alkyl is independently selected from -iso-propyl, -tert-butyl, -iso-butyl or -sec-butyl.
23. The compound of claim 3, wherein:
R1 is -halo, —C(halo)3, or —CH3;
n is 1 or 2;
m is 0; and
Ar2 is
24. The compound of claim 23, wherein R1 is —F, —Cl, —CF3 or —CH3.
25. The compound of claim 23, wherein r is 0, 1 or 2 and when r is 1 or 2 Ar2 is substituted at its para-position with an R8 group.
26. The compound of claim 25, wherein each R8 is independently selected from -halo, -cyclohexyl, -tert-butoxy, -iso-propoxy, —CF3, —OCF3, or —(C1-C6)alkyl, wherein optionally each R8 —(C1-C6)alkyl is independently selected from -iso-propyl, -tert-butyl, -iso-butyl or -sec-butyl.
27. The compound of claim 26, wherein n is 1 and R2 is —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C8)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.
28. The compound of claim 27, wherein R2 is —(C1-C10)alkyl substituted with two R5 groups.
29. The compound of claim 3, wherein:
R1 is -halo, —C(halo)3, or —CH3;
n is 1 or 2;
m is 1;
R3 is methyl; and
Ar2 is
30. The compound of claim 29, wherein R1 is —F, —Cl, —CF3 or —CH3.
31. The compound of claim 29, wherein r is 0, 1 or 2 and when r is 1 or 2 Ar2 is substituted at its para-position with an R8 group.
32. The compound of claim 31, wherein each R8 is independently selected from -halo, -cyclohexyl, -tert-butoxy, -iso-propoxy, —CF3, —OCF3, or —(C1-C6)alkyl, wherein optionally each R8 —(C1-C6)alkyl is independently selected from -iso-propyl, -tert-butyl, -iso-butyl or -sec-butyl.
33. The compound of claim 32, wherein n is 1 and R2 is —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10 )cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C8)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, —(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.
34. The compound of claim 33, wherein R2 is —(C1-C10)alkyl substituted with two R5 groups.
35. The compound of claim 3, wherein:
R1 is -halo, —C(halo)3, or —CH3;
n is 0, 1 or 2;
m is 0 or m is 1 and R3 is methyl; and
Ar2 is
36. The compound of claim 35, wherein R1 is —F, —Cl, —CF3 or —CH3.
37. The compound of claim 35, wherein s is 0 or 1.
38. The compound of claim 37, wherein n is 1 and R2 is —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C8)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.
39. The compound of claim 38, wherein R2 is —(C1-C10)alkyl substituted with two R5 groups.
40. The compound of claim 3, wherein:
R1 is -halo, —C(halo)3, or —CH3;
n is 0, 1 or 2;
m is 0 or m is 1 and R3 is methyl; and
Ar2 is
41. The compound of claim 40, wherein R1 is —F, —Cl, —CF3 or —CH3.
42. The compound of claim 40, wherein s is 0 or 1.
43. The compound of claim 42, wherein n is 1 and R2 is —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C8)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.
44. The compound of claim 43, wherein R2 is —(C1-C10)alkyl substituted with two R5 groups.
45. The compound of claim 11, wherein R1 is —F, —Cl, —CF3 or —CH3.
46. The compound of claim 12, wherein each R8 is independently selected from -halo, -cyclohexyl, -tert-butoxy, -iso-propoxy, —CF3, —OCF3, or —(C1-C6)alkyl, wherein optionally each R8 —(C1-C6)alkyl is independently selected from -iso-propyl, -tert-butyl, -iso-butyl or -sec-butyl.
47. The compound of claim 13, wherein R1 is —F, —Cl, —CF3 or —CH3.
48. The compound of claim 14, wherein each R8 is independently selected from -halo, -cyclohexyl, -tert-butoxy, -iso-propoxy, —CF3, —OCF3, or —(C1-C6)alkyl, wherein optionally each R8 —(C1-C6)alkyl is independently selected from -iso-propyl, -tert-butyl, -iso-butyl or -sec-butyl.
49. The compound of claim 10, wherein:
R1 is -halo, —C(halo)3, or —CH3;
n is 1 or 2;
m is 0; and
Ar2 is
50. The compound of claim 49, wherein R1 is —F, —Cl, —CF3 or —CH3.
51. The compound of claim 49, wherein r is 0, 1 or 2 and when r is 1 or 2 Ar2 is substituted at its para-position with an R8 group.
52. The compound of claim 51, wherein each R8 is independently selected from -halo, -cyclohexyl, -tert-butoxy, -iso-propoxy, —CF3, —OCF3, or —(C1-C6)alkyl, wherein optionally each R8 —(C1-C6)alkyl is independently selected from -iso-propyl, -tert-butyl, -iso-butyl or -sec-butyl.
53. The compound of claim 52, wherein n is 1 and R2 is —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C8)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.
54. The compound of claim 53, wherein R2 is —(C1-C10)alkyl substituted with two R5 groups.
55. The compound of claim 10, wherein:
R1 is -halo, —C(halo)3, or —CH3;
n is 1 or 2;
m is 1;
R3 is methyl; and
Ar2 is
56. The compound of claim 55, wherein R1 is —F, —Cl, —CF3 or —CH3.
57. The compound of claim 55, wherein r is 0, 1 or 2 and when r is 1 or 2 Ar2 is substituted at its para-position with an R8 group.
58. The compound of claim 57, wherein each R8 is independently selected from -halo, -cyclohexyl, -tert-butoxy, -iso-propoxy, —CF3, —OCF3, or —(C1-C6)alkyl, wherein optionally each R8 —(C1-C6)alkyl is independently selected from -iso-propyl, -tert-butyl, -iso-butyl or -sec-butyl.
59. The compound of claim 58, wherein n is 1 and R2 is —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C8)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.
60. The compound of claim 59, wherein R2 is —(C1-C10)alkyl substituted with two R5 groups.
61. The compound of claim 10, wherein:
R1 is -halo, —C(halo)3, or —CH3;
n is 0, 1 or 2;
m is 0 or m is 1 and R3 is methyl; and
Ar2 is
62. The compound of claim 61, wherein R1 is —F, —Cl, —CF3 or —CH3.
63. The compound of claim 61, wherein s is 0 or 1.
64. The compound of claim 63, wherein n is 1 and R2 is —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C8)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricyoloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.
65. The compound of claim 64, wherein R2 is —(C1-C10)alkyl substituted with two R5 groups.
66. The compound of claim 10, wherein:
R1 is -halo, —C(halo)3, or —CH3;
n is 0, 1 or 2;
m is 0 or m is 1 and R3 is methyl; and
Ar2 is
67. The compound of claim 66, wherein R1 is —F, —Cl, —CF3 or —CH3.
68. The compound of claim 66, wherein s is 0 or 1.
69. The compound of claim 68, wherein n is 1 and R2 is —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C8)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.
70. The compound of claim 69, wherein R2 is —(C1-C10)alkyl substituted with two R5 groups.
Description

This application claims the benefit of U.S. provisional application No. 60/533,037, filed Dec. 30, 2003, and International patent application no. PCT/US2004/042732, filed Dec. 17, 2004, the disclosure of each application being incorporated by reference herein in its entirety.

1. FIELD OF THE INVENTION

The present invention relates to Nitro(cyano)vinylpiperazine Compounds, compositions comprising an effective amount of a Nitro(cyano)vinylpiperazine Compound and methods for treating or preventing a condition, such as pain, comprising administering to an animal in need thereof an effective amount of a Nitro(cyano)vinylpiperazine Compound.

2. BACKGROUND OF THE INVENTION

Pain is the most common symptom for which patients seek medical advice and treatment. Pain can be acute or chronic. While acute pain is usually self-limited, chronic pain persists for 3 months or longer and can lead to significant changes in a patient's personality, lifestyle, functional ability and overall quality of life (K. M. Foley, Pain, in Cecil Textbook of Medicine 100-107 (J. C. Bennett and F. Plum eds., 20th ed. 1996)).

Moreover, chronic pain can be classified as either nociceptive or neuropathic. Nociceptive pain includes tissue injury-induced pain and inflammatory pain such as that associated with arthritis. Neuropathic pain is caused by damage to the peripheral or central nervous system and is maintained by aberrant somatosensory processing. There is a large body of evidence relating activity at both Group I mGluRs (mGluR1 and mGluR5) (M. E. Fundytus, CNS Drugs 15:29-58 (2001)) and vanilloid receptors (VR1) (V. Di Marzo et al., Current Opinion in Neurobiology 12:372-379 (2002)) to pain processing. Inhibiting GluR1 or mGluR5 reduces pain, as shown by in vivo treatment with antibodies selective for either GluR1 or mGluR5, where neuropathic pain in rats was attenuated (M. E. Fundytus et al., NeuroReport 9:731-735 (1998)). It has also been shown that antisense oligonucleotide knockdown of mGluR1 alleviates both neuropathic and inflammatory pain (M. E. Fundytus et al., British Journal of Pharmacology 132:354-367 (2001); M. E. Fundytus et al., Pharmacology, Biochemistry & Behavior 73:401-410 (2002)). Small molecule antagonists for mGluR5-attenuated pain in in vivo animal models are disclosed in, e.g., K. Walker et al., Neuropharmacology 40:1-9 (2000) and A. Dogrul et al., Neuroscience Letters 292:115-118 (2000)).

Nociceptive pain has been traditionally managed by administering non-opioid analgesics, such as acetylsalicylic acid, choline magnesium trisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, and naproxen; or opioid analgesics, including morphine, hydromorphone, methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. Id. In addition to the above-listed treatments, neuropathic pain, which can be difficult to treat, has also been treated with anti-epileptics (e.g., gabapentin, carbamazepine, valproic acid, topiramate, phenyloin), NMDA antagonists (e.g., ketamine, dextromethorphan), topical lidocaine (for post-herpetic neuralgia), and tricyclic antidepressants (e.g., fluoxetine, sertraline and amitriptyline).

Urinary incontinence (UI) is uncontrollable urination, generally caused by bladder-detrusor-muscle instability. UI affects people of all ages and levels of physical health, both in health care settings and in the community at large. Physiologic bladder contraction results in large part from acetylcholine-induced stimulation of post-ganglionic muscarinic-receptor sites on bladder smooth muscle. Treatments for UI include the administration of drugs having bladder-relaxant properties, which help to control bladder-detrusor-muscle overactivity. For example, anticholinergics such as propantheline bromide and glycopyrrolate, and combinations of smooth-muscle relaxants such as a combination of racemic oxybutynin and dicyclomine or an anticholinergic, have been used to treat UI (See, e.g., A. J. Wein, Urol. Clin. N. Am. 22:557-577 (1995); Levin et al., J. Urol. 128:396-398 (1982); Cooke et al., S. Afr. Med. J. 63:3 (1983); R. K. Mirakhur et al., Anaesthesia 38:1195-1204 (1983)). These drugs are not effective, however, in all patients having uninhibited bladder contractions. Administration of anticholinergic medications represent the mainstay of this type of treatment.

None of the existing commercial drug treatments for UI, however, has achieved complete success in all classes of UI patients, nor has treatment occurred without significant adverse side effects. For example, drowsiness, dry mouth, constipation, blurred vision, headaches, tachycardia, and cardiac arrhythmia, which are related to the anticholinergic activity of traditional anti-UI drugs, can occur frequently and adversely affect patient compliance. Yet despite the prevalence of unwanted anticholinergic effects in many patients, anticholinergic drugs are currently prescribed for patients having UI. The Merck Manual of Medical Information 631-634 (R. Berkow ed., 1997).

About 1 in 10 people develop an ulcer. Ulcers develop as a result of an imbalance between acid-secretory factors, also known as “aggressive factors,” such as stomach acid, pepsin, and Helicobacter pylori infection, and local mucosal-protective factors, such as secretion of bicarbonate, mucus, and prostaglandins.

Treatment of ulcers typically involves reducing or inhibiting the aggressive factors. For example, antacids such as aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, and calcium bicarbonate can be used to neutralize stomach acids. Antacids, however, can cause alkalosis, leading to nausea, headache, and weakness. Antacids can also interfere with the absorption of other drugs into the blood stream and cause diarrhea.

H2 antagonists, such as cimetidine, ranitidine, famotidine, and nizatidine, are also used to treat ulcers. H2 antagonists promote ulcer healing by reducing gastric acid and digestive-enzyme secretion elicited by histamine and other H2 agonists in the stomach and duodenum. H2 antagonists, however, can cause breast enlargement and impotence in men, mental changes (especially in the elderly), headache, dizziness, nausea, myalgia, diarrhea, rash, and fever.

H+, K+-ATPase inhibitors such as omeprazole and lansoprazole are also used to treat ulcers. H+, K+-ATPase inhibitors inhibit the production of enzymes used by the stomach to secrete acid. Side effects associated with H+, K+-ATPase inhibitors include nausea, diarrhea, abdominal colic, headache, dizziness, somnolence, skin rashes, and transient elevations of plasma activities of aminotransferases.

Sucraflate is also used to treat ulcers. Sucraflate adheres to epithelial cells and is believed to form a protective coating at the base of an ulcer to promote healing. Sucraflate, however, can cause constipation, dry mouth, and interfere with the absorption of other drugs.

Antibiotics are used when Helicobacter pylori is the underlying cause of the ulcer. Often antibiotic therapy is coupled with the administration of bismuth compounds such as bismuth subsalicylate and colloidal bismuth citrate. The bismuth compounds are believed to enhance secretion of mucous and HCO3 , inhibit pepsin activity, and act as an antibacterial against H. pylori. Ingestion of bismuth compounds, however, can lead to elevated plasma concentrations of Bi+3 and can interfere with the absorption of other drugs.

Prostaglandin analogues, such as misoprostal, inhibit secretion of acid and stimulate the secretion of mucous and bicarbonate and are also used to treat ulcers, especially ulcers in patients who require nonsteroidal anti-inflammatory drugs. Effective oral doses of prostaglandin analogues, however, can cause diarrhea and abdominal cramping. In addition, some prostaglandin analogues are abortifacients.

Carbenoxolone, a mineral corticoid, can also be used to treat ulcers. Carbenoxolone appears to alter the composition and quantity of mucous, thereby enhancing the mucosal barrier. Carbenoxolone, however, can lead to Na+ and fluid retention, hypertension, hypokalemia, and impaired glucose tolerance.

Muscarinic cholinergic antagonists such as pirenzapine and telenzapine can also be used to reduce acid secretion and treat ulcers. Side effects of muscarinic cholinergic antagonists include dry mouth, blurred vision, and constipation. The Merck Manual of Medical Information 496-500 (R. Berkow ed., 1997) and Goodman and Gilman's The Pharmacological Basis of Therapeutics 901-915 (J. Hardman and L. Limbird eds., 9th ed. 1996).

Inflammatory-bowel disease (IBD) is a chronic disorder in which the bowel becomes inflamed, often causing recurring abdominal cramps and diarrhea. The two types of IBD are Crohn's disease and ulcerative colitis.

Crohn's disease, which can include regional enteritis, granulomatous ileitis, and ileocolitis, is a chronic inflammation of the intestinal wall. Crohn's disease occurs equally in both sexes and is more common in Jews of eastern-European ancestry. Most cases of Crohn's disease begin before age 30 and the majority start between the ages of 14 and 24. The disease typically affects the full thickness of the intestinal wall. Generally the disease affects the lowest portion of the small intestine (ileum) and the large intestine, but can occur in any part of the digestive tract.

Early symptoms of Crohn's disease are chronic diarrhea, crampy abdominal pain, fever, loss of appetite, and weight loss. Complications associated with Crohn's disease include the development of intestinal obstructions, abnormal connecting channels (fistulas), and abscesses. The risk of cancer of the large intestine is increased in people who have Crohn's disease. Often Crohn's disease is associated with other disorders such as gallstones, inadequate absorption of nutrients, amyloidosis, arthritis, episcleritis, aphthous stomatitis, erythema nodosum, pyoderma gangrenosum, ankylosing spondylitis, sacroilitis, uveitis, and primary sclerosing cholangitis. There is no known cure for Crohn's disease.

Cramps and diarrhea, side effects associated with Crohn's disease, can be relieved by anticholinergic drugs, diphenoxylate, loperamide, deodorized opium tincture, or codeine. Generally, the drug is taken orally before a meal.

Broad-spectrum antibiotics are often administered to treat the symptoms of Crohn's disease. The antibiotic metronidazole is often administered when the disease affects the large intestine or causes abscesses and fistulas around the anus. Long-term use of metronidazole, however, can damage nerves, resulting in pins-and-needles sensations in the arms and legs. Sulfasalazine and chemically related drugs can suppress mild inflammation, especially in the large intestine. These drugs, however, are less effective in sudden, severe flare-ups. Corticosteroids, such as prednisone, reduce fever and diarrhea and relieve abdominal pain and tenderness. Long-term corticosteroid therapy, however, invariably results in serious side effects such as high blood-sugar levels, increased risk of infection, osteoporosis, water retention, and fragility of the skin. Drugs such as azathioprine and mercaptourine can compromise the immune system and are often effective for Crohn's disease in patients that do not respond to other drugs. These drugs, however, usually need 3 to 6 months before they produce benefits and can cause serious side effects such as allergy, pancreatitis, and low white-blood-cell count.

When Crohn's disease causes the intestine to be obstructed or when abscesses or fistulas do not heal, surgery can be necessary to remove diseased sections of the intestine. Surgery, however, does not cure the disease, and inflammation tends to recur where the intestine is rejoined. In almost half of the cases a second operation is needed. The Merck Manual of Medical Information 528-530 (R. Berkow ed., 1997).

Ulcerative colitis is a chronic disease in which the large intestine becomes inflamed and ulcerated, leading to episodes of bloody diarrhea, abdominal cramps, and fever. Ulcerative colitis usually begins between ages 15 and 30, however, a small group of people have their first attack between ages 50 and 70. Unlike Crohn's disease, ulcerative colitis never affects the small intestine and does not affect the full thickness of the intestine. The disease usually begins in the rectum and the sigmoid colon and eventually spreads partially or completely through out the large intestine. The cause of ulcerative colitis is unknown. Treatment of ulcerative colitis is directed to controlling inflammation, reducing symptoms, and replacing lost fluids and nutrients.

Irritable-bowel syndrome (IBS) is a disorder of motility of the entire gastrointestinal tract, causing abdominal pain, constipation, and/or diarrhea. IBS affects three-times more women than men.

There are two major types of IBS. The first type, spastic-colon type, is commonly triggered by eating, and usually produces periodic constipation and diarrhea with pain. Mucous often appears in the stool. The pain can come in bouts of continuous dull aching pain or cramps, usually in the lower abdomen. The person suffering from spastic-colon type IBS can also experience bloating, gas, nausea, headache, fatigue, depression, anxiety, and difficulty concentrating. The second type of IBS usually produces painless diarrhea or constipation. The diarrhea can begin suddenly and with extreme urgency. Often the diarrhea occurs soon after a meal and can sometimes occur immediately upon awakening.

Treatment of IBS typically involves modification of an IBS-patient's diet. Often it is recommended that an IBS patient avoid beans, cabbage, sorbitol, and fructose. A low-fat, high-fiber diet can also help some IBS patients. Regular physical activity can also help keep the gastrointestinal tract functioning properly. Drugs such as propantheline that slow the function of the gastrointestinal tract are generally not effective for treating IBS. Antidiarrheal drugs, such as diphenoxylate and loperamide, help with diarrhea. The Merck Manual of Medical Information 525-526 (R. Berkow ed., 1997).

Certain pharmaceutical agents have been administered for treating addiction. U.S. Pat. No. 5,556,838 to Mayer et al. discloses the use of nontoxic NMDA-blocking agents co-administered with an addictive substance to prevent the development of tolerance or withdrawal symptoms. U.S. Pat. No. 5,574,052 to Rose et al. discloses co-administration of an addictive substance with an antagonist to partially block the pharmacological effects of the substance. U.S. Pat. No. 5,075,341 to Mendelson et al. discloses the use of a mixed opiate agonist/antagonist to treat cocaine and opiate addiction. U.S. Pat. No. 5,232,934 to Downs discloses administration of 3-phenoxypyridine to treat addiction. U.S. Pat. Nos. 5,039,680 and 5,198,459 to Imperato et al. disclose using a serotonin antagonist to treat chemical addiction. U.S. Pat. No. 5,556,837 to Nestler et. al. discloses infusing BDNF or NT-4 growth factors to inhibit or reverse neurological adaptive changes that correlate with behavioral changes in an addicted individual. U.S. Pat. No. 5,762,925 to Sagan discloses implanting encapsulated adrenal medullary cells into an animal's central nervous system to inhibit the development of opioid intolerance. U.S. Pat. No. 6,204,284 to Beer et al. discloses racemic ()-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane for use in the prevention or relief of a withdrawal syndrome resulting from addiction to drugs and for the treatment of chemical dependencies.

Without treatment, Parkinson's disease progresses to a rigid akinetic state in which patients are incapable of caring for themselves. Death frequently results from complications of immobility, including aspiration pneumonia or pulmonary embolism. Drugs commonly used for the treatment of Parkinson's disease include carbidopa/levodopa, pergolide, bromocriptine, selegiline, amantadine, and trihexyphenidyl hydrochloride. There remains, however, a need for drugs useful for the treatment of Parkinson's disease and having an improved therapeutic profile.

Anxiety is a fear, apprehension, or dread of impending danger often accompanied by restlessness, tension, tachycardia, and dyspnea. Currently, benzodiazepines are the most commonly used anti-anxiety agents for generalized anxiety disorder. Benzodiazepines, however, carry the risk of producing impairment of cognition and skilled motor functions, particularly in the elderly, which can result in confusion, delerium, and falls with fractures. Sedatives are also commonly prescribed for treating anxiety. The azapirones, such as buspirone, are also used to treat moderate anxiety. The azapirones, however, are less useful for treating severe anxiety accompanied with panic attacks.

Epilepsy is a disorder characterized by the tendency to have recurring seizures. Examples of drugs for treating a seizure and epilepsy include carbamazepine, ethosuximide, gabapentin, lamotrignine, phenobarbital, phenyloin, primidone, valproic acid, trimethadione, bemzodiaepines, gabapentin, lamotrigine, γ-vinyl GABA, acetazolamide, and felbamate. Anti-seizure drugs, however, can have side effects such as drowsiness; hyperactivity; hallucinations; inability to concentrate; central and peripheral nervous system toxicity, such as nystagmus, ataxia, diplopia, and vertigo; gingival hyperplasia; gastrointestinal disturbances such as nausea, vomiting, epigastric pain, and anorexia; endocrine effects such as inhibition of antidiuretic hormone, hyperglycemia, glycosuria, osteomalacia; and hypersensitivity such as scarlatiniform rash, morbilliform rash, Stevens-Johnson syndrome, systemic lupus erythematosus, and hepatic necrosis; and hematological reactions such as red-cell aplasia, agranulocytosis, thrombocytopenia, aplastic anemia, and megaloblastic anemia. The Merck Manual of Medical Information 345-350 (R. Berkow ed., 1997).

Symptoms of strokes vary depending on what part of the brain is affected. Symptoms include loss or abnormal sensations in an arm or leg or one side of the body, weakness or paralysis of an arm or leg or one side of the body, partial loss of vision or hearing, double vision, dizziness, slurred speech, difficulty in thinking of the appropriate word or saying it, inability to recognize parts of the body, unusual movements, loss of bladder control, imbalance, and falling, and fainting. The symptoms can be permanent and can be associated with coma or stupor. Examples of drugs for treating strokes include anticoagulants such as heparin, drugs that break up clots such as streptokinase or tissue plasminogen activator, and drugs that reduce swelling such as mannitol or corticosteroids. The Merck Manual of Medical Information 352-355 (R. Berkow ed., 1997).

Pruritus is an unpleasant sensation that prompts scratching. Conventionally, pruritus is treated by phototherapy with ultraviolet B or PUVA or with therapeutic agents such as naltrexone, nalmefene, danazol, tricyclics, and antidepressants.

Selective antagonists of the metabotropic glutamate receptor 5 (“mGluR5”) have been shown to exert analgesic activity in in vivo animal models (K. Walker et al., Neuropharmacology 40:1-9 (2000) and A. Dogrul et al., Neuroscience Letters, 292(2):115-118 (2000)).

Selective antagonists of the mGluR5 receptor have also been shown to exert anxiolytic and anti-depressant activity in in vivo animal models (E. Tatarczynska et al., Br. J. Pharmacol. 132(7):1423-1430 (2001) and P. J. M. Will et al., Trends in Pharmacological Sciences 22(7):331-37 (2001)).

Selective antagonists of the mGluR5 receptor have also been shown to exert anti-Parkinson activity in vivo (K. J. Ossowska et al., Neuropharmacology 41(4):413-20 (2001) and P. J. M. Will et al., Trends in Pharmacological Sciences 22(7):331-37 (2001)).

Selective antagonists of the mGluR5 receptor have also been shown to exert anti-dependence activity in vivo (C. Chiamulera et al., Nature Neuroscience (9):873-74 (2001)).

There remains, however, a clear need in the art for new drugs useful for treating or preventing pain, UI, an ulcer, IBD, IBS, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington's chorea, amyotrophic lateral sclerosis (“ALS”), dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, or depression.

Citation of any reference in Section 2 of this application is not to be construed as an admission that such reference is prior art to the present application.

3. SUMMARY OF THE INVENTION

The present invention encompasses compounds of formula (I):


and pharmaceutically acceptable salts thereof, where:

Ar1 is

Ar2 is

R1 is —H, -halo, —CH3, —CN, —NO2, —OH, —OCH3, —NH2, —C(halo)3, —CH(halo)2, or —CH2(halo);

each R2 is independently:

(a) -halo, —OH, —NH2, —CN, or —NO2;

(b) —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C8)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or

(c) -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;

each R3 is independently:

(a) -halo, —OH, —NH2, —CN, or —NO2;

(b) —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or

(c) -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;

R4 is —H, —CN, —C(O)O(C1-C4)alkyl, or —C(O)NH((C1-C4)alkyl);

each R5 is independently —CN, —OH, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, -halo, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;

each R6 is independently —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, -halo, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;

each R7 is independently —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)3, —CH(halo)2, or —CH2(halo);

each R8 is independently —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, -halo, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;

each halo is independently —F, —Cl, —Br, or —I;

m is an integer ranging from 0 to 2;

n is an integer ranging from 0 to 3;

p is an integer ranging from 0 to 2;

q is an integer ranging from 0 to 6;

r is an integer ranging from 0 to 5; and

s is an integer ranging from 0 to 4.

The invention further encompasses compounds of formula (II):


and pharmaceutically acceptable salts thereof, where:

Ar1 is

R1 is —H, -halo, —CH3, —CN, —NO2, —OH, —OCH3, —NH2, —C(halo)3, —CH(halo)2, or —CH2(halo);

each R2 is independently:

(a) -halo, —OH, —NH2, —CN, or —NO2;

(b) —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C4)tricycloalkyl, —(C5-C8)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or

(c) -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;

each R3 is independently:

(a) -halo, —OH, —NH2, —CN, or —NO2;

(b) —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or

(c) -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;

R4 is —H, —CN, —C(O)O(C1-C4)alkyl, or —C(O)NH((C1-C4)alkyl);

each R5 is independently —CN, —OH, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, -halo, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;

each R6 is independently —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, -halo, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;

each R7 is independently —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)3, —CH(halo)2, or —CH2(halo);

each R9 is independently —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, -halo, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;

each halo is independently —F, —Cl, —Br, or —I;

m is an integer ranging from 0 to 2;

n is an integer ranging from 0 to 3;

p is an integer ranging from 0 to 2;

q is an integer ranging from 0 to 6;

r is an integer ranging from 0 to 5; and

s is an integer ranging from 0 to 4.

A compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof (a “Nitro(cyano)vinylpiperazine Compound”) is useful for treating or preventing pain, UI, an ulcer, IBD, IBS, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington's chorea, ALS, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, or depression (each being a “Condition”) in an animal.

The invention also relates to compositions comprising an effective amount of a Nitro(cyano)vinylpiperazine Compound and a pharmaceutically acceptable vehicle. The compositions are useful for treating or preventing a Condition in an animal.

The invention further relates to methods for treating a Condition, comprising administering to an animal in need thereof an effective amount of a Nitro(cyano)vinylpiperazine Compound.

The invention further relates to methods for preventing a Condition, comprising administering to an animal in need thereof an effective amount of a Nitro(cyano)vinylpiperazine Compound.

The invention still further relates to methods for inhibiting Vanilloid Receptor 1 (“VR1”) function in a cell, comprising contacting a cell capable of expressing VR1 with an effective amount of a Nitro(cyano)vinylpiperazine Compound.

The invention still further relates to methods for inhibiting mGluR5 function in a cell, comprising contacting a cell capable of expressing mGluR5 with an effective amount of a Nitro(cyano)vinylpiperazine Compound.

The invention still further relates to methods for inhibiting metabotropic glutamate receptor 1 (“mGluR1”) function in a cell, comprising contacting a cell capable of expressing mGluR1 with an effective amount of a Nitro(cyano)vinylpiperazine Compound.

The invention still further relates to methods for preparing a composition, comprising the step of admixing a Nitro(cyano)vinylpiperazine Compound and a pharmaceutically acceptable carrier or excipient.

The invention still further relates to a kit comprising a container containing an effective amount of a Nitro(cyano)vinylpiperazine Compound.

The present invention can be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments of the invention.

4. DETAILED DESCRIPTION OF THE INVENTION 4.1 Nitro(cyano)vinylpiperazine Compounds of Formula (I)

As stated above, the present invention encompasses Nitro(cyano)vinylpiperazine Compounds of formula (I)


where Ar1, Ar2, R3, R4, and m are defined above for the Nitro(cyano)vinylpiperazine Compounds of formula (I).

In one embodiment, Ar1 is a pyridyl group.

In another embodiment Ar1 is a pyrimidinyl group.

In another embodiment, Ar1 is a pyrazinyl group.

In another embodiment, Ar1 is a pyridazinyl group.

In another embodiment, Ar1 is a thiadiazolyl group.

In another embodiment, Ar2 is a benzoimidazolyl group.

In another embodiment, Ar2 is a benzothiazolyl group.

In another embodiment, Ar2 is a benzooxazolyl group.

In another embodiment, Ar2 is

In another embodiment, Ar2 is

In another embodiment, Ar2 is

In another embodiment, Ar2 is

In another embodiment, Ar2 is

In another embodiment, Ar2 is

In another embodiment, Ar2 is

In another embodiment, m is 0.

In another embodiment, m is 1.

In another embodiment, m is 2.

In another embodiment, n is 0.

In another embodiment, n is 1.

In another embodiment, n is 2.

In another embodiment, n is 3.

In another embodiment, p is 0.

In another embodiment, p is 1.

In another embodiment, p is 2.

In another embodiment, r is 0.

In another embodiment, r is 1.

In another embodiment, r is 2.

In another embodiment, r is 3.

In another embodiment, r is 4.

In another embodiment, r is 5.

In another embodiment, q is 0.

In another embodiment, q is 1.

In another embodiment, q is 2.

In another embodiment, q is 3.

In another embodiment, q is 4.

In another embodiment, q is 5.

In another embodiment, q is 6.

In another embodiment, s is 0.

In another embodiment, s is 1.

In another embodiment, s is 2.

In another embodiment, s is 3.

In another embodiment, s is 4.

In another embodiment, R1 is —H.

In another embodiment, R1 is -halo.

In another embodiment, R1 is —Cl.

In another embodiment, R1 is —Br.

In another embodiment, R1 is —I.

In another embodiment, R1 is —F.

In another embodiment, R1 is —CH3.

In another embodiment, R1 is —CN.

In another embodiment, R1 is —NO2.

In another embodiment, R1 is —OH.

In another embodiment, R1 is —OCH3.

In another embodiment, R1 is —NH2.

In another embodiment, R1 is —C(halo)3.

In another embodiment, R1 is —CH(halo)2.

In another embodiment, R1 is —CH2(halo).

In another embodiment, R1 is —CF3.

In another embodiment, n or p is 1 and R2 is -halo, —OH, —NH2, —CN, or —NO2.

In another embodiment, n or p is 1 and R2 is —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C8)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.

In another embodiment, n or p is 1 and R2 is -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups.

In another embodiment, m is 1 and R3 is -halo, —OH, —NH2, —CN, or —NO2;

In another embodiment, m is 1 and R3 is —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.

In another embodiment, m is 1 and R3 is -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups.

In another embodiment, m is 1 and R3 is —(C1-C10)alkyl.

In another embodiment, m is 1, R3 is —(C1-C10)alkyl, and the carbon atom to which the R3 group is attached is in the (R) configuration.

In another embodiment, m is 1, R3 is —(C1-C10)alkyl, and the carbon atom to which the R3 group is attached is in the (S) configuration.

In another embodiment, m is 1 and R3 is —CH3.

In another embodiment, m is 1, R3 is —CH3, and the carbon atom to which the R3 group is attached is in the (R) configuration.

In another embodiment, m is 1, R3 is —CH3, and the carbon atom to which the R3 group is attached is in the (S) configuration.

In another embodiment, m is 1 and R3 is -halo.

In another embodiment, m is 1 and R3 is —Cl.

In another embodiment, m is 1 and R3 is —Br.

In another embodiment, m is 1 and R3 is —I.

In another embodiment, m is 1 and R3 is —F.

In another embodiment, R4 is —H.

In another embodiment, R4 is —CN.

In another embodiment, R4 is —C(O)O(C1-C4)alkyl.

In another embodiment, R2 is or —C(O)NH((C1-C4)alkyl).

In another embodiment, Ar2 is a benzothiazolyl group and s is 1.

In another embodiment, Ar2 is a benzoimidazolyl group and s is 1.

In another embodiment, Ar2 is a benzooxazolyl group and s is 1.

In another embodiment, Ar2 is


and s is 1.

In another embodiment, Ar2 is


and s is 1.

In another embodiment, Ar2 is


and r is 1.

In another embodiment, Ar2 is


and q is 1.

In another embodiment, Ar2 is


and r is 1.

In another embodiment, Ar2 is


and r is 1.

In another embodiment, Ar2 is


and r is 1.

In another embodiment, Ar1 is a pyridyl group, m is 0, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyridyl group, m is 0, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyridyl group, m is 0, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyridyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, r is 1, m is 0, Ar2 is


and R8 is a —(C1-C6)alkyl. In another embodiment, the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridyl group, r is 1, m is 0, Ar2 is


and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridyl group, r is 1, m is 0, Ar2 is


and R8 is -halo. In another embodiment, the -halo is substituted at the phenyl group's para-position. In another embodiment, -halo is —Cl. In another embodiment, -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, -halo is —Br. In another embodiment, -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, -halo is —I. In another embodiment, -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, -halo is —F. In another embodiment, -halo is —F and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrazinyl group, m is 0, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyrazinyl group, m is 0, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyrazinyl group, m is 0, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyrazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, r is 1, m is 0, Ar2 is


and R8 is a —(C1-C6)alkyl. In another embodiment, the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrazinyl group, r is 1, m is 0, Ar2 is


and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrazinyl group, r is 1, m is 0, Ar2 is


and R8 is -halo. In another embodiment, the -halo is substituted at the phenyl group's para-position. In another embodiment, -halo is —Cl. In another embodiment, -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, -halo is —Br. In another embodiment, -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, -halo is —I. In another embodiment, -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, -halo is —F. In another embodiment, -halo is —F and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrimidinyl group, m is 0, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyrimidinyl group, m is 0, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyrimidinyl group, m is 0, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyrimidinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, r is 1, m is 0, Ar2 is


and R8 is a —(C1-C6)alkyl. In another embodiment, the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrimidinyl group, r is 1, m is 0, Ar2 is


and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrimidinyl group, r is 1, m is 0, Ar2 is


and R8 is -halo. In another embodiment, the -halo is substituted at the phenyl group's para-position. In another embodiment, -halo is —Cl. In another embodiment, -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, -halo is —Br. In another embodiment, -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, -halo is —I. In another embodiment, -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, -halo is —F. In another embodiment, -halo is —F and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridazinyl group, m is 0, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, m is 0, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, m is 0, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, r is 1, m is 0, Ar2 is


and R8 is a —(C1-C6)alkyl. In another embodiment, the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridazinyl group, r is 1, m is 0, Ar2 is


and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridazinyl group, r is 1, m is 0, Ar2 is


and R8 is -halo. In another embodiment, the -halo is substituted at the phenyl group's para-position. In another embodiment, -halo is —Cl. In another embodiment, -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, -halo is —Br. In another embodiment, -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, -halo is —I. In another embodiment, -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, -halo is —F. In another embodiment, -halo is —F and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a thiadiazolyl group, m is 0, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a thiadiazolyl group, m is 0, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a thiadiazolyl group, m is 0, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a thiadiazolyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, r is 1, m is 0, Ar2 is


and R8 is a —(C1-C6)alkyl. In another embodiment, the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a thiadiazolyl group, r is 1, m is 0, Ar2 is


and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a thiadiazolyl group, r is 1, m is 0, Ar2 is


and R8 is -halo. In another embodiment, the -halo is substituted at the phenyl group's para-position. In another embodiment, -halo is —Cl. In another embodiment, -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, -halo is —Br. In another embodiment, -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, -halo is —I. In another embodiment, -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, -halo is —F. In another embodiment, -halo is —F and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridyl group, m is 1, R3 is —CH3, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyridyl group, m is 1, R3 is —CH3, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyridyl group, m is 1, R3 is —CH3, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyridyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is a —(C1-C6)alkyl. In another embodiment, the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is -halo. In another embodiment, the -halo is substituted at the phenyl group's para-position. In another embodiment, -halo is —Cl. In another embodiment, -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, -halo is —Br. In another embodiment, -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, -halo is —I. In another embodiment, -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, -halo is —F. In another embodiment, -halo is —F and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrazinyl group, m is 1, R3 is —CH3, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyrazinyl group, m is 1, R3 is —CH3, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyrazinyl group, m is 1, R3 is —CH3, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyrazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is a —(C1-C6)alkyl. In another embodiment, the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrazinyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrazinyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is -halo. In another embodiment, the -halo is substituted at the phenyl group's para-position. In another embodiment, -halo is —Cl. In another embodiment, -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, -halo is —Br. In another embodiment, -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, -halo is —I. In another embodiment, -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, -halo is —F. In another embodiment, -halo is —F and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrimidinyl group, m is 1, R3 is —CH3, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyrimidinyl group, m is 1, R3 is —CH3, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyrimidinyl group, m is 1, R3 is —CH3, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyrimidinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is a —(C1-C6)alkyl. In another embodiment, the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrimidinyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrimidinyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is -halo. In another embodiment, the -halo is substituted at the phenyl group's para-position. In another embodiment, -halo is —Cl. In another embodiment, -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, -halo is —Br. In another embodiment, -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, -halo is —I. In another embodiment, -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, -halo is —F. In another embodiment, -halo is —F and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridazinyl group, m is 1, R3 is —CH3, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, m is 1, R3 is —CH3, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, m is 1, R3 is —CH3, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is a —(C1-C6)alkyl. In another embodiment, the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridazinyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridazinyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is -halo. In another embodiment, the -halo is substituted at the phenyl group's para-position. In another embodiment, -halo is —Cl. In another embodiment, -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, -halo is —Br. In another embodiment, -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, -halo is —I. In another embodiment, -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, -halo is —F. In another embodiment, -halo is —F and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a thiadiazolyl group, m is 1, R3 is —CH3, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a thiadiazolyl group, m is 1, R3 is —CH3, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a thiadiazolyl group, m is 1, R3 is —CH3, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a thiadiazolyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, r is 1, m is 1, R3 is —CH, Ar2 is


and R8 is a —(C1-C6)alkyl. In another embodiment, the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a thiadiazolyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a thiadiazolyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is -halo. In another embodiment, the -halo is substituted at the phenyl group's para-position. In another embodiment, -halo is —Cl. In another embodiment, -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, -halo is —Br. In another embodiment, -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, -halo is —I. In another embodiment, -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, -halo is —F. In another embodiment, -halo is —F and is substituted at the phenyl group's para-position.

4.2 Nitro(cyano)vinylpiperazine Compounds of Formula (II)

The present invention further encompasses Nitro(cyano)vinylpiperazine Compounds of formula (II)


where Ar1, Ar2, R3, R4, and m are defined above for the Nitro(cyano)vinylpiperazine Compounds of formula (II).

In one embodiment, Ar1 is a pyridyl group.

In another embodiment Ar1 is a pyrimidinyl group.

In another embodiment, Ar1 is a pyrazinyl group.

In another embodiment, Ar1 is a pyridazinyl group.

In another embodiment, Ar1 is a thiadiazolyl group.

In another embodiment, Ar2 is a benzoimidazolyl group.

In another embodiment, Ar2 is a benzothiazolyl group.

In another embodiment, Ar2 is a benzooxazolyl group.

In another embodiment, Ar2 is

In another embodiment, Ar2 is

In another embodiment, Ar2 is

In another embodiment, Ar2 is

In another embodiment, Ar2 is

In another embodiment, Ar2 is

In another embodiment, Ar2 is

In another embodiment, m is 0.

In another embodiment, m is 1.

In another embodiment, m is 2.

In another embodiment, n is 0.

In another embodiment, n is 1.

In another embodiment, n is 2.

In another embodiment, n is 3.

In another embodiment, p is 0.

In another embodiment, p is 1.

In another embodiment, p is 2.

In another embodiment, r is 0.

In another embodiment, r is 1.

In another embodiment, r is 2.

In another embodiment, r is 3.

In another embodiment, r is 4.

In another embodiment, r is 5.

In another embodiment, q is 0.

In another embodiment, q is 1.

In another embodiment, q is 2.

In another embodiment, q is 3.

In another embodiment, q is 4.

In another embodiment, q is 5.

In another embodiment, q is 6.

In another embodiment, s is 0.

In another embodiment, s is 1.

In another embodiment, s is 2.

In another embodiment, s is 3.

In another embodiment, s is 4.

In another embodiment, R1 is —H.

In another embodiment, R1 is -halo.

In another embodiment, R1 is —Cl.

In another embodiment, R1 is —Br.

In another embodiment, R1 is —I.

In another embodiment, R1 is —F.

In another embodiment, R1 is —CH3.

In another embodiment, R1 is —CN.

In another embodiment, R1 is —NO2.

In another embodiment, R1 is —OH.

In another embodiment, R1 is —OCH3.

In another embodiment, R1 is —NH2.

In another embodiment, R1 is —CH(halo)3.

In another embodiment, R1 is —CH(halo)2.

In another embodiment, R1 is —CH2(halo).

In another embodiment, R1 is —CF3.

In another embodiment, n or p is 1 and R2 is -halo, —OH, —NH2, —CN, or —NO2.

In another embodiment, n or p is 1 and R2 is —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C8)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.

In another embodiment, n or p is 1 and R2 is -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups.

In another embodiment, m is 1 and R3 is -halo, —OH, —NH2, —CN, or —NO2;

In another embodiment, m is 1 and R3 is —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.

In another embodiment, m is 1 and R3 is -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups.

In another embodiment, m is 1 and R3 is —(C1-C10)alkyl.

In another embodiment, m is 1, R3 is —(C1-C10)alkyl, and the carbon atom to which the R3 group is attached is in the (R) configuration.

In another embodiment, m is 1, R3 is —(C1-C10)alkyl, and the carbon atom to which the R3 group is attached is in the (S) configuration.

In another embodiment, m is 1 and R3 is —CH3.

In another embodiment, m is 1, R3 is —CH3, and the carbon atom to which the R3 group is attached is in the (R) configuration.

In another embodiment, m is 1, R3 is —CH3, and the carbon atom to which the R3 group is attached is in the (S) configuration.

In another embodiment, m is 1 and R3 is -halo.

In another embodiment, m is 1 and R3 is —Cl.

In another embodiment, m is 1 and R3 is —Br.

In another embodiment, m is 1 and R3 is —I.

In another embodiment, m is 1 and R3 is —F.

In another embodiment, R4 is —H.

In another embodiment, R4 is —CN.

In another embodiment, R4 is —C(O)O(C1-C4)alkyl.

In another embodiment, R4 is or —C(O)NH((C1-C4)alkyl).

In another embodiment, Ar2 is a benzothiazolyl group and s is 1.

In another embodiment, Ar2 is a benzoimidazolyl group and s is 1.

In another embodiment, Ar2 is a benzooxazolyl group and s is 1.

In another embodiment, Ar2 is


and s is 1.

In another embodiment, Ar2 is


and s is 1.

In another embodiment, Ar2 is


and r is 1.

In another embodiment, Ar2 is


and q is 1.

In another embodiment, Ar2 is


and r is 1.

In another embodiment, Ar2 is


and r is 1.

In another embodiment, Ar2 is


and r is 1.

In another embodiment, Ar1 is a pyridyl group, m is 0, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyridyl group, m is 0, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyridyl group, m is 0, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyridyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, r is 1, m is 0, Ar2 is


and R8 is a —(C1-C6)alkyl. In another embodiment, the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridyl group, r is 1, m is 0, Ar2 is


and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridyl group, r is 1, m is 0, Ar2 is


and R8 is -halo. In another embodiment, the -halo is substituted at the phenyl group's para-position. In another embodiment, -halo is —Cl. In another embodiment, -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, -halo is —Br. In another embodiment, -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, -halo is —I. In another embodiment, -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, -halo is —F. In another embodiment, -halo is —F and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrazinyl group, m is 0, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyrazinyl group, m is 0, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyrazinyl group, m is 0, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyrazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, r is 1, m is 0, Ar2 is


and R8 is a —(C1-C6)alkyl. In another embodiment, the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrazinyl group, r is 1, m is 0, Ar2 is


and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrazinyl group, r is 1, m is 0, Ar2 is


and R8 is -halo. In another embodiment, the -halo is substituted at the phenyl group's para-position. In another embodiment, -halo is —Cl. In another embodiment, -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, -halo is —Br. In another embodiment, -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, -halo is —I. In another embodiment, -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, -halo is —F. In another embodiment, -halo is —F and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrimidinyl group, m is 0, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyrimidinyl group, m is 0, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyrimidinyl group, m is 0, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyrimidinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, r is 1, m is 0, Ar2 is


and R8 is a —(C1-C6)alkyl. In another embodiment, the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrimidinyl group, r is 1, m is 0, Ar2 is


and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrimidinyl group, r is 1, m is 0, Ar2 is


and R8 is -halo. In another embodiment, the -halo is substituted at the phenyl group's para-position. In another embodiment, -halo is —Cl. In another embodiment, -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, -halo is —Br. In another embodiment, -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, -halo is —I. In another embodiment, -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, -halo is —F. In another embodiment, -halo is —F and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridazinyl group, m is 0, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, m is 0, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, m is 0, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, r is 1, m is 0, Ar2 is


and R8 is a —(C1-C6)alkyl. In another embodiment, the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridazinyl group, r is 1, m is 0, Ar2 is


and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridazinyl group, r is 1, m is 0, Ar2 is


and R8 is -halo. In another embodiment, the -halo is substituted at the phenyl group's para-position. In another embodiment, -halo is —Cl. In another embodiment, -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, -halo is —Br. In another embodiment, -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, -halo is —I. In another embodiment, -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, -halo is —F. In another embodiment, -halo is —F and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a thiadiazolyl group, m is 0, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a thiadiazolyl group, m is 0, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a thiadiazolyl group, m is 0, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a thiadiazolyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, m is 0, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, r is 1, m is 0, Ar2 is


and R8 is a —(C1-C6)alkyl. In another embodiment, the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a thiadiazolyl group, r is 1, m is 0, Ar2 is


and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a thiadiazolyl group, r is 1, m is 0, Ar2 is


and R8 is -halo. In another embodiment, the -halo is substituted at the phenyl group's para-position. In another embodiment, -halo is —Cl. In another embodiment, -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, -halo is —Br. In another embodiment, -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, -halo is —I. In another embodiment, -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, -halo is —F. In another embodiment, -halo is —F and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridyl group, m is 1, R3 is —CH3, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyridyl group, m is 1, R3 is —CH3, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyridyl group, m is 1, R3 is —CH3, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyridyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is a —(C1-C6)alkyl. In another embodiment, the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is -halo. In another embodiment, the -halo is substituted at the phenyl group's para-position. In another embodiment, -halo is —Cl. In another embodiment, -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, -halo is —Br. In another embodiment, -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, -halo is —I. In another embodiment, -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, -halo is —F. In another embodiment, -halo is —F and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrazinyl group, m is 1, R3 is —CH3, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyrazinyl group, m is 1, R3 is —CH3, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyrazinyl group, m is 1, R3 is —CH3, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyrazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrazinyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is a —(C1-C6)alkyl. In another embodiment, the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrazinyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrazinyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is -halo. In another embodiment, the -halo is substituted at the phenyl group's para-position. In another embodiment, -halo is —Cl. In another embodiment, -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, -halo is —Br. In another embodiment, -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, -halo is —I. In another embodiment, -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, -halo is —F. In another embodiment, -halo is —F and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrimidinyl group, m is 1, R3 is —CH3, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyrimidinyl group, m is 1, R3 is —CH3, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyrimidinyl group, m is 1, R3 is —CH3, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyrimidinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyrimidinyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is a —(C1-C6)alkyl. In another embodiment, the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrimidinyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrimidinyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is -halo. In another embodiment, the -halo is substituted at the phenyl group's para-position. In another embodiment, -halo is —Cl. In another embodiment, -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, -halo is —Br. In another embodiment, -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, -halo is —I. In another embodiment, -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, -halo is —F. In another embodiment, -halo is —F and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridazinyl group, m is 1, R3 is —CH3, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, m is 1, R3 is —CH3, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, m is 1, R3 is —CH3, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is a —(C1-C6)alkyl. In another embodiment, the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridazinyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridazinyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is -halo. In another embodiment, the -halo is substituted at the phenyl group's para-position. In another embodiment, -halo is —Cl. In another embodiment, -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, -halo is —Br. In another embodiment, -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, -halo is —I. In another embodiment, -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, -halo is —F. In another embodiment, -halo is —F and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a thiadiazolyl group, m is 1, R3 is —CH3, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a thiadiazolyl group, m is 1, R3 is —CH3, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a thiadiazolyl group, m is 1, R3 is —CH3, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a thiadiazolyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, m is 1, R3 is —CH3, and Ar2 is

In another embodiment, Ar1 is a thiadiazolyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is a —(C1-C6)alkyl. In another embodiment, the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, the —(C1-C6)alkyl is an iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a thiadiazolyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a thiadiazolyl group, r is 1, m is 1, R3 is —CH3, Ar2 is


and R8 is -halo. In another embodiment, the -halo is substituted at the phenyl group's para-position. In another embodiment, -halo is —Cl. In another embodiment, -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, -halo is —Br. In another embodiment, -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, -halo is —I. In another embodiment, -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, -halo is —F. In another embodiment, -halo is —F and is substituted at the phenyl group's para-position.

4.3 Nitro(cyano)vinylpiperazine Compounds of Formula (I) and (II)

Certain Nitro(cyano)vinylpiperazine Compounds can have asymmetric centers and therefore exist in different enantiomeric and diastereomic forms. This invention relates to the use of all optical isomers and stereoisomers of the Nitro(cyano)vinylpiperazine Compounds, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment that may employ or contain them.

The Nitro(cyano)vinylpiperazine Compounds have a double bond to which is bonded an R4 group and AR2—NH— group, each of which can be cis or trans relative to the other. Accordingly, the present invention encompasses Nitro(cyano)vinylpiperazine Compounds in which the R4 group and the Ar2—NH— group are cis relative to each other, Nitro(cyano)vinylpiperazine Compounds in which the R4 group and the Ar2—NH— group are trans relative to each other, and all mixtures thereof. Formula (I) and (II) are intended to encompass: (i) Nitro(cyano)vinylpiperazine Compounds in which the R4 group and the Ar2—NH— group are trans relative to each other, (ii) Nitro(cyano)vinylpiperazine Compounds in which the R4 group and the Ar2—NH— group are cis relative to each other, and (iii) all mixtures thereof.

In the Nitro(cyano)vinylpiperazine Compounds each R3 can be attached to any carbon of the piperazine ring. In one embodiment, the Nitro(cyano)vinylpiperazine Compounds have only one R3 group, i.e., m=1, and that R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R3 group, and that R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr2)═C(CN)(R4) group or —C(NHAr2)═C(NO2)(R4) group.

In another embodiment, two R3 groups are attached to a single carbon atom of the piperazine ring. In another embodiment, an R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group and another R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr2)═C(CN)(R4) group or —C(NHAr2)═C(NO2)(R4) group.

In another embodiment, the Nitro(cyano)vinylpiperazine Compound has two R3 groups, i.e., m=2, each being attached to a different carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has two R3 groups, each being attached to a different carbon atom adjacent to the nitrogen atom attached to the —C(NHAr2)═C(CN)(R4) group or —C(NHAr2)═C(NO2)(R4) group.

In one embodiment, where the Nitro(cyano)vinylpiperazine Compound has one or two R3 groups, a carbon atom to which an R3 group is attached has the (R) configuration. In another embodiment, where the Nitro(cyano)vinylpiperazine Compound has one or two R3 groups, a carbon atom to which the R3 group is attached has the (S) configuration. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R3 groups, and at least one of the carbon atoms to which an R3 group is attached has the (R) configuration. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R3 groups, and at least one of the carbon atoms to which an R3 group is attached has the (S) configuration.

In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, and the carbon to which the R3 group is attached is in the (R) configuration. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is —(C1-C4)alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R3 groups, an R3 group is attached to carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is —CH3. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is —CF3. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is —CH2CH3.

In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr2)═C(CN)(R4) group or —C(NHAr2)═C(NO2)(R4) group, and the carbon to which the R3 group is attached is in the (R) configuration. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr2)═C(CN)(R4) group or —C(NHAr2)═C(NO2)(R4) group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is —(C1-C4)alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr2)═C(CN)(R4) group or —C(NHAr2)═C(NO2)(R4) group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is —CH3. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to the nitrogen attached to the —C(NHAr2)═C(CN)(R4) group or —C(NHAr2)═C(NO2)(R4) group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is —CF3. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr2)═C(CN)(R4) group or —C(NHAr2)═C(NO2)(R4) group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is —CH2CH3.

In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, and the carbon to which the R3 group is attached is in the (S) configuration. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is —(C1-C4)alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is —CH3. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is —CF3. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is —CH2CH3.

In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr2)═C(CN)(R4) group or —C(NHAr2)═C(NO2)(R4) group, and the carbon to which the R3 group is attached is in the (S) configuration. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr2)═C(CN)(R4) group or —C(NHAr2)═C(NO2)(R4) group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is —(C1-C4)alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr2)═C(CN)(R4) group or —C(NHAr2)═C(NO2)(R4) group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is —CH3. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr2)═C(CN)(R4) group or —C(NHAr2)═C(NO2)(R4) group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is —CF3. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr2)═C(CN)(R4) group or —C(NHAr2)═C(NO2)(R4) group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is —CH2CH3.

In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, and the carbon to which the R3 group is attached is in the (R) configuration. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is —(C1-C4)alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is —CH3. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is —CF3. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is —CH2CH3.

In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr2)═C(CN)(R4) group or —C(NHAr2)═C(NO2)(R4) group, and the carbon to which the R3 group is attached is in the (R) configuration. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr2)═C(CN)(R4) group or —C(NHAr2)═C(NO2)(R4) group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is —(C1-C4)alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr2)═C(CN)(R4) group or —C(NHAr2)═C(NO2)(R4) group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is —CH3. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr2)═C(CN)(R4) group or —C(NHAr2)═C(NO2)(R4) group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is —CF3. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr2)═C(CN)(R4) group or —C(NHAr2)═C(NO2)(R4) group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is —CH2CH3.

In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, and the carbon to which the R3 group is attached is in the (S) configuration. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is —(C1-C4)alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is —CH3. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is —CF3. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is —CH2CH3.

In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr2)═C(CN)(R4) group or —C(NHAr2)═C(NO2)(R4) group, and the carbon to which the R3 group is attached is in the (S) configuration. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr2)═C(CN)(R4) group or —C(NHAr2)═C(NO2)(R4) group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is —(C1-C4)alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr2)═C(CN)(R4) group or —C(NHAr2)═C(NO2)(R4) group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is —CH3. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr2)═C(CN)(R4) group or —C(NHAr2)═C(NO2)(R4) group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is —CF3. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr2)═C(CN)(R4) group or —C(NHAr2)═C(NO2)(R4) group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is —CH2CH3.

The bonds represented by a

line in the Nitro(cyano)vinylpiperazine compounds of Formula (I) and Formula (II) mean that the R4 group and the Ar2—NH— group can be cis relative to each other, trans relative to each other, or a mixture of the cis- and trans-isomers. 4.4 Illustrative Nitro(cyano)vinylpiperazine Compounds

Illustrative Nitro(cyano)vinylpiperazine Compounds are listed below in Tables 1-7.

For the chemical structure depicted, e.g., at the head of each of Tables 1-7, a is independently 0 or 1. When a=0, the group at the “a” position is —H. When a=1, the group at the “a” position (R8a) is other than —H, i.e., is R8.

TABLE 1
(III)
and pharmaceutically acceptable salts thereof, where:
Compound Ar1 R8a
A1 (a, b, c, and d) -2-(3-chloropyridyl) -tert-butyl
A2 (a, b, c, and d) -2-(3-chloropyridyl) -iso-butyl
A3 (a, b, c, and d) -2-(3-chloropyridyl) -sec-butyl
A4 (a, b, c, and d) -2-(3-chloropyridyl) -cyclohexyl
A5 (a, b, c, and d) -2-(3-chloropyridyl) -tert-butoxy
A6 (a, b, c, and d) -2-(3-chloropyridyl) -iso-propoxy
A7 (a, b, c, and d) -2-(3-chloropyridyl) —CF3
A8 (a, b, c, and d) -2-(3-chloropyridyl) —OCF3
A9 (a, b, c, and d) -2-(3-chloropyridyl) —Cl
A10 (a, b, c, and d) -2-(3-chloropyridyl) —Br
A11 (a, b, c, and d) -2-(3-chloropyridyl) —I
A12 (a, b, c, and d) -2-(3-chloropyridyl) -n-butyl
A13 (a, b, c, and d) -2-(3-chloropyridyl) -n-propyl
A14 (a, b, c, and d) -2-(3-chloropyridyl) -iso-propyl
A15 (a, b, c, and d) -2-(3-fluoropyridyl) -tert-butyl
A16 (a, b, c, and d) -2-(3-fluoropyridyl) -iso-butyl
A17 (a, b, c, and d) -2-(3-fluoropyridyl) -sec-butyl
A18 (a, b, c, and d) -2-(3-fluoropyridyl) -cyclohexyl
A19 (a, b, c, and d) -2-(3-fluoropyridyl) -tert-butoxy
A20 (a, b, c, and d) -2-(3-fluoropyridyl) -iso-propoxy
A21 (a, b, c, and d) -2-(3-fluoropyridyl) —CF3
A22 (a, b, c, and d) -2-(3-fluoropyridyl) —OCF3
A23 (a, b, c, and d) -2-(3-fluoropyridyl) —Cl
A24 (a, b, c, and d) -2-(3-fluoropyridyl) —Br
A25 (a, b, c, and d) -2-(3-fluoropyridyl) —I
A26 (a, b, c, and d) -2-(3-fluoropyridyl) -n-butyl
A27 (a, b, c, and d) -2-(3-fluoropyridyl) -n-propyl
A28 (a, b, c, and d) -2-(3-fluoropyridyl) -iso-propyl
A29 (a, b, c, and d) -2-(3-methylpyridyl) -tert-butyl
A30 (a, b, c, and d) -2-(3-methylpyridyl) -iso-butyl
A31 (a, b, c, and d) -2-(3-methylpyridyl) -sec-butyl
A32 (a, b, c, and d) -2-(3-methylpyridyl) -cyclohexyl
A33 (a, b, c, and d) -2-(3-methylpyridyl) -tert-butoxy
A34 (a, b, c, and d) -2-(3-methylpyridyl) -iso-propoxy
A35 (a, b, c, and d) -2-(3-methylpyridyl) —CF3
A36 (a, b, c, and d) -2-(3-methylpyridyl) —OCF3
A37 (a, b, c, and d) -2-(3-methylpyridyl) —Cl
A38 (a, b, c, and d) -2-(3-methylpyridyl) —Br
A39 (a, b, c, and d) -2-(3-methylpyridyl) —I
A40 (a, b, c, and d) -2-(3-methylpyridyl) -n-butyl
A41 (a, b, c, and d) -2-(3-methylpyridyl) -n-propyl
A42 (a, b, c, and d) -2-(3-methylpyridyl) -iso-propyl
A43 (a, b, c, and d) -2-(3-CF3-pyridyl) -tert-butyl
A44 (a, b, c, and d) -2-(3-CF3-pyridyl) -iso-butyl
A45 (a, b, c, and d) -2-(3-CF3-pyridyl) -sec-butyl
A46 (a, b, c, and d) -2-(3-CF3-pyridyl) -cyclohexyl
A47 (a, b, c, and d) -2-(3-CF3-pyridyl) -tert-butoxy
A48 (a, b, c, and d) -2-(3-CF3-pyridyl) -iso-propoxy
A49 (a, b, c, and d) -2-(3-CF3-pyridyl) —CF3
A50 (a, b, c, and d) -2-(3-CF3-pyridyl) —OCF3
A51 (a, b, c, and d) -2-(3-CF3-pyridyl) —Cl
A52 (a, b, c, and d) -2-(3-CF3-pyridyl) —Br
A53 (a, b, c, and d) -2-(3-CF3-pyridyl) —I
A54 (a, b, c, and d) -2-(3-CF3-pyridyl) -n-butyl
A55 (a, b, c, and d) -2-(3-CF3-pyridyl) -n-propyl
A56 (a, b, c, and d) -2-(3-CF3-pyridyl) -iso-propyl
A57 (a, b, c, and d) -2-(3-CHF2-pyridyl) -tert-butyl
A58 (a, b, c, and d) -2-(3-CHF2-pyridyl) -iso-butyl
A59 (a, b, c, and d) -2-(3-CHF2-pyridyl) -sec-butyl
A60 (a, b, c, and d) -2-(3-CHF2-pyridyl) -cyclohexyl
A61 (a, b, c, and d) -2-(3-CHF2-pyridyl) -tert-butoxy
A62 (a, b, c, and d) -2-(3-CHF2-pyridyl) -iso-propoxy
A63 (a, b, c, and d) -2-(3-CHF2-pyridyl) —CF3
A64 (a, b, c, and d) -2-(3-CHF2-pyridyl) —OCF3
A65 (a, b, c, and d) -2-(3-CHF2-pyridyl) —Cl
A66 (a, b, c, and d) -2-(3-CHF2-pyridyl) —Br
A67 (a, b, c, and d) -2-(3-CHF2-pyridyl) —I
A68 (a, b, c, and d) -2-(3-CHF2-pyridyl) -n-butyl
A69 (a, b, c, and d) -2-(3-CHF2-pyridyl) -n-propyl
A70 (a, b, c, and d) -2-(3-CHF2-pyridyl) -iso-propyl
A71 (a, b, c, and d) -2-(3-hydroxypyridyl) -tert-butyl
A72 (a, b, c, and d) -2-(3-hydroxypyridyl) -iso-butyl
A73 (a, b, c, and d) -2-(3-hydroxypyridyl) -sec-butyl
A74 (a, b, c, and d) -2-(3-hydroxypyridyl) -cyclohexyl
A75 (a, b, c, and d) -2-(3-hydroxypyridyl) -tert-butoxy
A76 (a, b, c, and d) -2-(3-hydroxypyridyl) -iso-propoxy
A77 (a, b, c, and d) -2-(3-hydroxypyridyl) —CF3
A78 (a, b, c, and d) -2-(3-hydroxypyridyl) —OCF3
A79 (a, b, c, and d) -2-(3-hydroxypyridyl) —Cl
A80 (a, b, c, and d) -2-(3-hydroxypyridyl) —Br
A81 (a, b, c, and d) -2-(3-hydroxypyridyl) —I
A82 (a, b, c, and d) -2-(3-hydroxypyridyl) -n-butyl
A83 (a, b, c, and d) -2-(3-hydroxypyridyl) -n-propyl
A84 (a, b, c, and d) -2-(3-hydroxypyridyl) -iso-propyl
A85 (a, b, c, and d) -2-(3-nitropyridyl) -tert-butyl
A86 (a, b, c, and d) -2-(3-nitropyridyl) -iso-butyl
A87 (a, b, c, and d) -2-(3-nitropyridyl) -sec-butyl
A88 (a, b, c, and d) -2-(3-nitropyridyl) -cyclohexyl
A89 (a, b, c, and d) -2-(3-nitropyridyl) -tert-butoxy
A90 (a, b, c, and d) -2-(3-nitropyridyl) -iso-propoxy
A91 (a, b, c, and d) -2-(3-nitropyridyl) —CF3
A92 (a, b, c, and d) -2-(3-nitropyridyl) —OCF3
A93 (a, b, c, and d) -2-(3-nitropyridyl) —Cl
A94 (a, b, c, and d) -2-(3-nitropyridyl) —Br
A95 (a, b, c, and d) -2-(3-nitropyridyl) —I
A96 (a, b, c, and d) -2-(3-nitropyridyl) -n-butyl
A97 (a, b, c, and d) -2-(3-nitropyridyl) -n-propyl
A98 (a, b, c, and d) -2-(3-nitropyridyl) -iso-propyl
A99 (a, b, c, and d) -2-(3-cyanopyridyl) -tert-butyl
A100 (a, b, c, and d) -2-(3-cyanopyridyl) -iso-butyl
A101 (a, b, c, and d) -2-(3-cyanopyridyl) -sec-butyl
A102 (a, b, c, and d) -2-(3-cyanopyridyl) -cyclohexyl
A103 (a, b, c, and d) -2-(3-cyanopyridyl) -tert-butoxy
A104 (a, b, c, and d) -2-(3-cyanopyridyl) -iso-propoxy
A105 (a, b, c, and d) -2-(3-cyanopyridyl) —CF3
A106 (a, b, c, and d) -2-(3-cyanopyridyl) —OCF3
A107 (a, b, c, and d) -2-(3-cyanopyridyl) —Cl
A108 (a, b, c, and d) -2-(3-cyanopyridyl) —Br
A109 (a, b, c, and d) -2-(3-cyanopyridyl) —I
A110 (a, b, c, and d) -2-(3-cyanopyridyl) -n-butyl
A111 (a, b, c, and d) -2-(3-cyanopyridyl) -n-propyl
A112 (a, b, c, and d) -2-(3-cyanopyridyl) -isopropyl
A113 (a, b, c, and d) -2-(3-bromopyridyl) -tert-butyl
A114 (a, b, c, and d) -2-(3-bromopyridyl) -iso-butyl
A115 (a, b, c, and d) -2-(3-bromopyridyl) -sec-butyl
A116 (a, b, c, and d) -2-(3-bromopyridyl) -cyclohexyl
A117 (a, b, c, and d) -2-(3-bromopyridyl) -tert-butoxy
A118 (a, b, c, and d) -2-(3-bromopyridyl) -iso-propoxy
A119 (a, b, c, and d) -2-(3-bromopyridyl) —CF3
A120 (a, b, c, and d) -2-(3-bromopyridyl) —OCF3
A121 (a, b, c, and d) -2-(3-bromopyridyl) —Cl
A122 (a, b, c, and d) -2-(3-bromopyridyl) —Br
A123 (a, b, c, and d) -2-(3-bromopyridyl) —I
A124 (a, b, c, and d) -2-(3-bromopyridyl) -n-butyl
A125 (a, b, c, and d) -2-(3-bromopyridyl) -n-propyl
A126 (a, b, c, and d) -2-(3-bromopyridyl) -iso-propyl
A127 (a, b, c, and d) -2-(3-iodopyridyl) -tert-butyl
A128 (a, b, c, and d) -2-(3-iodopyridyl) -iso-butyl
A129 (a, b, c, and d) -2-(3-iodopyridyl) -sec-butyl
A130 (a, b, c, and d) -2-(3-iodopyridyl) -cyclohexyl
A131 (a, b, c, and d) -2-(3-iodopyridyl) -tert-butoxy
A132 (a, b, c, and d) -2-(3-iodopyridyl) -iso-propoxy
A133 (a, b, c, and d) -2-(3-iodopyridyl) —CF3
A134 (a, b, c, and d) -2-(3-iodopyridyl) —OCF3
A135 (a, b, c, and d) -2-(3-iodopyridyl) —Cl
A136 (a, b, c, and d) -2-(3-iodopyridyl) —Br
A137 (a, b, c, and d) -2-(3-iodopyridyl) —I
A138 (a, b, c, and d) -2-(3-iodopyridyl) -n-butyl
A139 (a, b, c, and d) -2-(3-iodopyridyl) -n-propyl
A140 (a, b, c, and d) -2-(3-iodopyridyl) -iso-propyl
A141 (a, b, c, and d) -4-(5-chloropyrimidinyl) -tert-butyl
A142 (a, b, c, and d) -4-(5-chloropyrimidinyl) -iso-butyl
A143 (a, b, c, and d) -4-(5-chloropyrimidinyl) -sec-butyl
A144 (a, b, c, and d) -4-(5-chloropyrimidinyl) -cyclohexyl
A145 (a, b, c, and d) -4-(5-chloropyrimidinyl) -tert-butoxy
A146 (a, b, c, and d) -4-(5-chloropyrimidinyl) -iso-propoxy
A147 (a, b, c, and d) -4-(5-chloropyrimidinyl) —CF3
A148 (a, b, c, and d) -4-(5-chloropyrimidinyl) —OCF3
A149 (a, b, c, and d) -4-(5-chloropyrimidinyl) —Cl
A150 (a, b, c, and d) -4-(5-chloropyrimidinyl) —Br
A151 (a, b, c, and d) -4-(5-chloropyrimidinyl) —I
A152 (a, b, c, and d) -4-(5-chloropyrimidinyl) -n-butyl
A153 (a, b, c, and d) -4-(5-chloropyrimidinyl) -n-propyl
A154 (a, b, c, and d) -4-(5-chloropyrimidinyl) -iso-propyl
A155 (a, b, c, and d) -4-(5-methylpyrimidinyl) -tert-butyl
A156 (a, b, c, and d) -4-(5-methylpyrimidinyl) -iso-butyl
A157 (a, b, c, and d) -4-(5-methylpyrimidinyl) -sec-butyl
A158 (a, b, c, and d) -4-(5-methylpyrimidinyl) -cyclohexyl
A159 (a, b, c, and d) -4-(5-methylpyrimidinyl) -tert-butoxy
A160 (a, b, c, and d) -4-(5-methylpyrimidinyl) -iso-propoxy
A161 (a, b, c, and d) -4-(5-methylpyrimidinyl) —CF3
A162 (a, b, c, and d) -4-(5-methylpyrimidinyl) —OCF3
A163 (a, b, c, and d) -4-(5-methylpyrimidinyl) —Cl
A164 (a, b, c, and d) -4-(5-methylpyrimidinyl) —Br
A165 (a, b, c, and d) -4-(5-methylpyrimidinyl) —I
A166 (a, b, c, and d) -4-(5-methylpyrimidinyl) -n-butyl
A167 (a, b, c, and d) -4-(5-methylpyrimidinyl) -n-propyl
A168 (a, b, c, and d) -4-(5-methylpyrimidinyl) -iso-propyl
A169 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -tert-butyl
A170 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -iso-butyl
A171 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -sec-butyl
A172 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -cyclohexyl
A173 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -tert-butoxy
A174 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -iso-propoxy
A175 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —CF3
A176 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —OCF3
A177 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —Cl
A178 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —Br
A179 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —I
A180 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -n-butyl
A181 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -n-propyl
A182 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -iso-propyl
A183 (a, b, c, and d) -2-(3-chloropyrazinyl) -tert-butyl
A184 (a, b, c, and d) -2-(3-chloropyrazinyl) -iso-butyl
A185 (a, b, c, and d) -2-(3-chloropyrazinyl) -sec-butyl
A186 (a, b, c, and d) -2-(3-chloropyrazinyl) -cyclohexyl
A187 (a, b, c, and d) -2-(3-chloropyrazinyl) -tert-butoxy
A188 (a, b, c, and d) -2-(3-chloropyrazinyl) -iso-propoxy
A189 (a, b, c, and d) -2-(3-chloropyrazinyl) —CF3
A190 (a, b, c, and d) -2-(3-chloropyrazinyl) —OCF3
A191 (a, b, c, and d) -2-(3-chloropyrazinyl) —Cl
A192 (a, b, c, and d) -2-(3-chloropyrazinyl) —Br
A193 (a, b, c, and d) -2-(3-chloropyrazinyl) —I
A194 (a, b, c, and d) -2-(3-chloropyrazinyl) -n-butyl
A195 (a, b, c, and d) -2-(3-chloropyrazinyl) -n-propyl
A196 (a, b, c, and d) -2-(3-chloropyrazinyl) -iso-propyl
A197 (a, b, c, and d) -2-(3-methylpyrazinyl) -tert-butyl
A198 (a, b, c, and d) -2-(3-methylpyrazinyl) -iso-butyl
A199 (a, b, c, and d) -2-(3-methylpyrazinyl) -sec-butyl
A200 (a, b, c, and d) -2-(3-methylpyrazinyl) -cyclohexyl
A201 (a, b, c, and d) -2-(3-methylpyrazinyl) -tert-butoxy
A202 (a, b, c, and d) -2-(3-methylpyrazinyl) -iso-propoxy
A203 (a, b, c, and d) -2-(3-methylpyrazinyl) —CF3
A204 (a, b, c, and d) -2-(3-methylpyrazinyl) —OCF3
A205 (a, b, c, and d) -2-(3-methylpyrazinyl) —Cl
A206 (a, b, c, and d) -2-(3-methylpyrazinyl) —Br
A207 (a, b, c, and d) -2-(3-methylpyrazinyl) —I
A208 (a, b, c, and d) -2-(3-methylpyrazinyl) -n-butyl
A209 (a, b, c, and d) -2-(3-methylpyrazinyl) -n-propyl
A210 (a, b, c, and d) -2-(3-methylpyrazinyl) -iso-propyl
A211 (a, b, c, and d) -2-(3-fluoropyrazinyl) -tert-butyl
A212 (a, b, c, and d) -2-(3-fluoropyrazinyl) -iso-butyl
A213 (a, b, c, and d) -2-(3-fluoropyrazinyl) -sec-butyl
A214 (a, b, c, and d) -2-(3-fluoropyrazinyl) -cyclohexyl
A215 (a, b, c, and d) -2-(3-fluoropyrazinyl) -tert-butoxy
A216 (a, b, c, and d) -2-(3-fluoropyrazinyl) -iso-propoxy
A217 (a, b, c, and d) -2-(3-fluoropyrazinyl) —CF3
A218 (a, b, c, and d) -2-(3-fluoropyrazinyl) —OCF3
A219 (a, b, c, and d) -2-(3-fluoropyrazinyl) —Cl
A220 (a, b, c, and d) -2-(3-fluoropyrazinyl) —Br
A221 (a, b, c, and d) -2-(3-fluoropyrazinyl) —I
A222 (a, b, c, and d) -2-(3-fluoropyrazinyl) -n-butyl
A223 (a, b, c, and d) -2-(3-fluoropyrazinyl) -n-propyl
A224 (a, b, c, and d) -2-(3-fluoropyrazinyl) -iso-propyl
A225 (a, b, c, and d) -3-(4-chloropyridazinyl) -tert-butyl
A226 (a, b, c, and d) -3-(4-chloropyridazinyl) -iso-butyl
A227 (a, b, c, and d) -3-(4-chloropyridazinyl) -sec-butyl
A228 (a, b, c, and d) -3-(4-chloropyridazinyl) -cyclohexyl
A229 (a, b, c, and d) -3-(4-chloropyridazinyl) -tert-butoxy
A230 (a, b, c, and d) -3-(4-chloropyridazinyl) -iso-propoxy
A231 (a, b, c, and d) -3-(4-chloropyridazinyl) —CF3
A232 (a, b, c, and d) -3-(4-chloropyridazinyl) —OCF3
A233 (a, b, c, and d) -3-(4-chloropyridazinyl) —Cl
A234 (a, b, c, and d) -3-(4-chloropyridazinyl) —Br
A235 (a, b, c, and d) -3-(4-chloropyridazinyl) —I
A236 (a, b, c, and d) -3-(4-chloropyridazinyl) -n-butyl
A237 (a, b, c, and d) -3-(4-chloropyridazinyl) -n-propyl
A238 (a, b, c, and d) -3-(4-chloropyridazinyl) -iso-propyl
A239 (a, b, c, and d) -3-(4-methylpyridazinyl) -tert-butyl
A240 (a, b, c, and d) -3-(4-methylpyridazinyl) -iso-butyl
A241 (a, b, c, and d) -3-(4-methylpyridazinyl) -sec-butyl
A242 (a, b, c, and d) -3-(4-methylpyridazinyl) -cyclohexyl
A243 (a, b, c, and d) -3-(4-methylpyridazinyl) -tert-butoxy
A244 (a, b, c, and d) -3-(4-methylpyridazinyl) -iso-propoxy
A245 (a, b, c, and d) -3-(4-methylpyridazinyl) —CF3
A246 (a, b, c, and d) -3-(4-methylpyridazinyl) —OCF3
A247 (a, b, c, and d) -3-(4-methylpyridazinyl) —Cl
A248 (a, b, c, and d) -3-(4-methylpyridazinyl) —Br
A249 (a, b, c, and d) -3-(4-methylpyridazinyl) —I
A250 (a, b, c, and d) -3-(4-methylpyridazinyl) -n-butyl
A251 (a, b, c, and d) -3-(4-methylpyridazinyl) -n-propyl
A252 (a, b, c, and d) -3-(4-methylpyridazinyl) -iso-propyl
A253 (a, b, c, and d) -3-(4-fluoropyridazinyl) -tert-butyl
A254 (a, b, c, and d) -3-(4-fluoropyridazinyl) -iso-butyl
A255 (a, b, c, and d) -3-(4-fluoropyridazinyl) -sec-butyl
A256 (a, b, c, and d) -3-(4-fluoropyridazinyl) -cyclohexyl
A257 (a, b, c, and d) -3-(4-fluoropyridazinyl) -tert-butoxy
A258 (a, b, c, and d) -3-(4-fluoropyridazinyl) -iso-propoxy
A259 (a, b, c, and d) -3-(4-fluoropyridazinyl) —CF3
A260 (a, b, c, and d) -3-(4-fluoropyridazinyl) —OCF3
A261 (a, b, c, and d) -3-(4-fluoropyridazinyl) —Cl
A262 (a, b, c, and d) -3-(4-fluoropyridazinyl) —Br
A263 (a, b, c, and d) -3-(4-fluoropyridazinyl) —I
A264 (a, b, c, and d) -3-(4-fluoropyridazinyl) -n-butyl
A265 (a, b, c, and d) -3-(4-fluoropyridazinyl) -n-propyl
A266 (a, b, c, and d) -3-(4-fluoropyridazinyl) -iso-propyl
A267 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -tert-butyl
A268 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -iso-butyl
A269 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -sec-butyl
A270 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -cyclohexyl
A271 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -tert-butoxy
A272 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -iso-propoxy
A273 (a, b, c, and d) -5-(4-chlorothiadiazolyl) —CF3
A274 (a, b, c, and d) -5-(4-chlorothiadiazolyl) —OCF3
A275 (a, b, c, and d) -5-(4-chlorothiadiazolyl) —Cl
A276 (a, b, c, and d) -5-(4-chlorothiadiazolyl) —Br
A277 (a, b, c, and d) -5-(4-chlorothiadiazolyl) —I
A278 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -n-butyl
A279 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -n-propyl
A280 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -iso-propyl
A281 (a, b, c, and d) -5-(4-methylthiadiazolyl) -tert-butyl
A282 (a, b, c, and d) -5-(4-methylthiadiazolyl) -iso-butyl
A283 (a, b, c, and d) -5-(4-methylthiadiazolyl) -sec-butyl
A284 (a, b, c, and d) -5-(4-methylthiadiazolyl) -cyclohexyl
A285 (a, b, c, and d) -5-(4-methylthiadiazolyl) -tert-butoxy
A286 (a, b, c, and d) -5-(4-methylthiadiazolyl) -iso-propoxy
A287 (a, b, c, and d) -5-(4-methylthiadiazolyl) —CF3
A288 (a, b, c, and d) -5-(4-methylthiadiazolyl) —OCF3
A289 (a, b, c, and d) -5-(4-methylthiadiazolyl) —Cl
A290 (a, b, c, and d) -5-(4-methylthiadiazolyl) —Br
A291 (a, b, c, and d) -5-(4-methylthiadiazolyl) —I
A292 (a, b, c, and d) -5-(4-methylthiadiazolyl) -n-butyl
A293 (a, b, c, and d) -5-(4-methylthiadiazolyl) -n-propyl
A294 (a, b, c, and d) -5-(4-methylthiadiazolyl) -iso-propyl
A295 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -tert-butyl
A296 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -iso-butyl
A297 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -sec-butyl
A298 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -cyclohexyl
A299 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -tert-butoxy
A300 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -iso-propoxy
A301 (a, b, c, and d) -5-(4-fluorothiadiazolyl) —CF3
A302 (a, b, c, and d) -5-(4-fluorothiadiazolyl) —OCF3
A303 (a, b, c, and d) -5-(4-fluorothiadiazolyl) —Cl
A304 (a, b, c, and d) -5-(4-fluorothiadiazolyl) —Br
A305 (a, b, c, and d) -5-(4-fluorothiadiazolyl) —I
A306 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -n-butyl
A307 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -n-propyl
A308 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -iso-propyl
“a” means R3 is —H.
“b” means R3 is —CH3 and the Nitro(cyano)vinylpiperazine Compound is racemic.
“c” means R3 is —CH3 and the carbon atom to which R3 is attached is in the (R) configuration.
“d” means R3 is —CH3 and the carbon atom to which R3 is attached is in the (S) configuration.

TABLE 2
(IV)
and pharmaceutically acceptable salts thereof, where:
Compound Ar1 R8a
B1 (a, b, c, and d) -2-(3-chloropyridyl) -tert-butyl
B2 (a, b, c, and d) -2-(3-chloropyridyl) -iso-butyl
B3 (a, b, c, and d) -2-(3-chloropyridyl) -sec-butyl
B4 (a, b, c, and d) -2-(3-chloropyridyl) -cyclohexyl
B5 (a, b, c, and d) -2-(3-chloropyridyl) -tert-butoxy
B6 (a, b, c, and d) -2-(3-chloropyridyl) -iso-propoxy
B7 (a, b, c, and d) -2-(3-chloropyridyl) —CF3
B8 (a, b, c, and d) -2-(3-chloropyridyl) —OCF3
B9 (a, b, c, and d) -2-(3-chloropyridyl) —Cl
B10 (a, b, c, and d) -2-(3-chloropyridyl) —Br
B11 (a, b, c, and d) -2-(3-chloropyridyl) —I
B12 (a, b, c, and d) -2-(3-chloropyridyl) -n-butyl
B13 (a, b, c, and d) -2-(3-chloropyridyl) -n-propyl
B14 (a, b, c, and d) -2-(3-chloropyridyl) -iso-propyl
B15 (a, b, c, and d) -2-(3-fluoropyridyl) -tert-butyl
B16 (a, b, c, and d) -2-(3-fluoropyridyl) -iso-butyl
B17 (a, b, c, and d) -2-(3-fluoropyridyl) -sec-butyl
B18 (a, b, c, and d) -2-(3-fluoropyridyl) -cyclohexyl
B19 (a, b, c, and d) -2-(3-fluoropyridyl) -tert-butoxy
B20 (a, b, c, and d) -2-(3-fluoropyridyl) -iso-propoxy
B21 (a, b, c, and d) -2-(3-fluoropyridyl) —CF3
B22 (a, b, c, and d) -2-(3-fluoropyridyl) —OCF3
B23 (a, b, c, and d) -2-(3-fluoropyridyl) —Cl
B24 (a, b, c, and d) -2-(3-fluoropyridyl) —Br
B25 (a, b, c, and d) -2-(3-fluoropyridyl) —I
B26 (a, b, c, and d) -2-(3-fluoropyridyl) -n-butyl
B27 (a, b, c, and d) -2-(3-fluoropyridyl) -n-propyl
B28 (a, b, c, and d) -2-(3-fluoropyridyl) -iso-propyl
B29 (a, b, c, and d) -2-(3-methylpyridyl) -tert-butyl
B30 (a, b, c, and d) -2-(3-methylpyridyl) -iso-butyl
B31 (a, b, c, and d) -2-(3-methylpyridyl) -sec-butyl
B32 (a, b, c, and d) -2-(3-methylpyridyl) -cyclohexyl
B33 (a, b, c, and d) -2-(3-methylpyridyl) -tert-butoxy
B34 (a, b, c, and d) -2-(3-methylpyridyl) -iso-propoxy
B35 (a, b, c, and d) -2-(3-methylpyridyl) —CF3
B36 (a, b, c, and d) -2-(3-methylpyridyl) —OCF3
B37 (a, b, c, and d) -2-(3-methylpyridyl) —Cl
B38 (a, b, c, and d) -2-(3-methylpyridyl) —Br
B39 (a, b, c, and d) -2-(3-methylpyridyl) —I
B40 (a, b, c, and d) -2-(3-methylpyridyl) -n-butyl
B41 (a, b, c, and d) -2-(3-methylpyridyl) -n-propyl
B42 (a, b, c, and d) -2-(3-methylpyridyl) -iso-propyl
B43 (a, b, c, and d) -2-(3-CF3-pyridyl) -tert-butyl
B44 (a, b, c, and d) -2-(3-CF3-pyridyl) -iso-butyl
B45 (a, b, c, and d) -2-(3-CF3-pyridyl) -sec-butyl
B46 (a, b, c, and d) -2-(3-CF3-pyridyl) -cyclohexyl
B47 (a, b, c, and d) -2-(3-CF3-pyridyl) -tert-butoxy
B48 (a, b, c, and d) -2-(3-CF3-pyridyl) -iso-propoxy
B49 (a, b, c, and d) -2-(3-CF3-pyridyl) —CF3
B50 (a, b, c, and d) -2-(3-CF3-pyridyl) —OCF3
B51 (a, b, c, and d) -2-(3-CF3-pyridyl) —Cl
B52 (a, b, c, and d) -2-(3-CF3-pyridyl) —Br
B53 (a, b, c, and d) -2-(3-CF3-pyridyl) —I
B54 (a, b, c, and d) -2-(3-CF3-pyridyl) -n-butyl
B55 (a, b, c, and d) -2-(3-CF3-pyridyl) -n-propyl
B56 (a, b, c, and d) -2-(3-CF3-pyridyl) -iso-propyl
B57 (a, b, c, and d) -2-(3-CHF2-pyridyl) -tert-butyl
B58 (a, b, c, and d) -2-(3-CHF2-pyridyl) -iso-butyl
B59 (a, b, c, and d) -2-(3-CHF2-pyridyl) -sec-butyl
B60 (a, b, c, and d) -2-(3-CHF2-pyridyl) -cyclohexyl
B61 (a, b, c, and d) -2-(3-CHF2-pyridyl) -tert-butoxy
B62 (a, b, c, and d) -2-(3-CHF2-pyridyl) -iso-propoxy
B63 (a, b, c, and d) -2-(3-CHF2-pyridyl) —CF3
B64 (a, b, c, and d) -2-(3-CHF2-pyridyl) —OCF3
B65 (a, b, c, and d) -2-(3-CHF2-pyridyl) —Cl
B66 (a, b, c, and d) -2-(3-CHF2-pyridyl) —Br
B67 (a, b, c, and d) -2-(3-CHF2-pyridyl) —I
B68 (a, b, c, and d) -2-(3-CHF2-pyridyl) -n-butyl
B69 (a, b, c, and d) -2-(3-CHF2-pyridyl) -n-propyl
B70 (a, b, c, and d) -2-(3-CHF2-pyridyl) -iso-propyl
B71 (a, b, c, and d) -2-(3-hydroxypyridyl) -tert-butyl
B72 (a, b, c, and d) -2-(3-hydroxypyridyl) -iso-butyl
B73 (a, b, c, and d) -2-(3-hydroxypyridyl) -sec-butyl
B74 (a, b, c, and d) -2-(3-hydroxypyridyl) -cyclohexyl
B75 (a, b, c, and d) -2-(3-hydroxypyridyl) -tert-butoxy
B76 (a, b, c, and d) -2-(3-hydroxypyridyl) -iso-propoxy
B77 (a, b, c, and d) -2-(3-hydroxypyridyl) —CF3
B78 (a, b, c, and d) -2-(3-hydroxypyridyl) —OCF3
B79 (a, b, c, and d) -2-(3-hydroxypyridyl) —Cl
B80 (a, b, c, and d) -2-(3-hydroxypyridyl) —Br
B81 (a, b, c, and d) -2-(3-hydroxypyridyl) —I
B82 (a, b, c, and d) -2-(3-hydroxypyridyl) -n-butyl
B83 (a, b, c, and d) -2-(3-hydroxypyridyl) -n-propyl
B84 (a, b, c, and d) -2-(3-hydroxypyridyl) -iso-propyl
B85 (a, b, c, and d) -2-(3-nitropyridyl) -tert-butyl
B86 (a, b, c, and d) -2-(3-nitropyridyl) -iso-butyl
B87 (a, b, c, and d) -2-(3-nitropyridyl) -sec-butyl
B88 (a, b, c, and d) -2-(3-nitropyridyl) -cyclohexyl
B89 (a, b, c, and d) -2-(3-nitropyridyl) -tert-butoxy
B90 (a, b, c, and d) -2-(3-nitropyridyl) -iso-propoxy
B91 (a, b, c, and d) -2-(3-nitropyridyl) —CF3
B92 (a, b, c, and d) -2-(3-nitropyridyl) —OCF3
B93 (a, b, c, and d) -2-(3-nitropyridyl) —Cl
B94 (a, b, c, and d) -2-(3-nitropyridyl) —Br
B95 (a, b, c, and d) -2-(3-nitropyridyl) —I
B96 (a, b, c, and d) -2-(3-nitropyridyl) -n-butyl
B97 (a, b, c, and d) -2-(3-nitropyridyl) -n-propyl
B98 (a, b, c, and d) -2-(3-nitropyridyl) -iso-propyl
B99 (a, b, c, and d) -2-(3-cyanopyridyl) -tert-butyl
B100 (a, b, c, and d) -2-(3-cyanopyridyl) -iso-butyl
B101 (a, b, c, and d) -2-(3-cyanopyridyl) -sec-butyl
B102 (a, b, c, and d) -2-(3-cyanopyridyl) -cyclohexyl
B103 (a, b, c, and d) -2-(3-cyanopyridyl) -tert-butoxy
B104 (a, b, c, and d) -2-(3-cyanopyridyl) -iso-propoxy
B105 (a, b, c, and d) -2-(3-cyanopyridyl) —CF3
B106 (a, b, c, and d) -2-(3-cyanopyridyl) —OCF3
B107 (a, b, c, and d) -2-(3-cyanopyridyl) —Cl
B108 (a, b, c, and d) -2-(3-cyanopyridyl) —Br
B109 (a, b, c, and d) -2-(3-cyanopyridyl) —I
B110 (a, b, c, and d) -2-(3-cyanopyridyl) -n-butyl
B111 (a, b, c, and d) -2-(3-cyanopyridyl) -n-propyl
B112 (a, b, c, and d) -2-(3-cyanopyridyl) -isopropyl
B113 (a, b, c, and d) -2-(3-bromopyridyl) -tert-butyl
B114 (a, b, c, and d) -2-(3-bromopyridyl) -iso-butyl
B115 (a, b, c, and d) -2-(3-bromopyridyl) -sec-butyl
B116 (a, b, c, and d) -2-(3-bromopyridyl) -cyclohexyl
B117 (a, b, c, and d) -2-(3-bromopyridyl) -tert-butoxy
B118 (a, b, c, and d) -2-(3-bromopyridyl) -iso-propoxy
B119 (a, b, c, and d) -2-(3-bromopyridyl) —CF3
B120 (a, b, c, and d) -2-(3-bromopyridyl) —OCF3
B121 (a, b, c, and d) -2-(3-bromopyridyl) —Cl
B122 (a, b, c, and d) -2-(3-bromopyridyl) —Br
B123 (a, b, c, and d) -2-(3-bromopyridyl) —I
B124 (a, b, c, and d) -2-(3-bromopyridyl) -n-butyl
B125 (a, b, c, and d) -2-(3-bromopyridyl) -n-propyl
B126 (a, b, c, and d) -2-(3-bromopyridyl) -iso-propyl
B127 (a, b, c, and d) -2-(3-iodopyridyl) -tert-butyl
B128 (a, b, c, and d) -2-(3-iodopyridyl) -iso-butyl
B129 (a, b, c, and d) -2-(3-iodopyridyl) -sec-butyl
B130 (a, b, c, and d) -2-(3-iodopyridyl) -cyclohexyl
B131 (a, b, c, and d) -2-(3-iodopyridyl) -tert-butoxy
B132 (a, b, c, and d) -2-(3-iodopyridyl) -iso-propoxy
B133 (a, b, c, and d) -2-(3-iodopyridyl) —CF3
B134 (a, b, c, and d) -2-(3-iodopyridyl) —OCF3
B135 (a, b, c, and d) -2-(3-iodopyridyl) —Cl
B136 (a, b, c, and d) -2-(3-iodopyridyl) —Br
B137 (a, b, c, and d) -2-(3-iodopyridyl) —I
B138 (a, b, c, and d) -2-(3-iodopyridyl) -n-butyl
B139 (a, b, c, and d) -2-(3-iodopyridyl) -n-propyl
B140 (a, b, c, and d) -2-(3-iodopyridyl) -iso-propyl
B141 (a, b, c, and d) -4-(5-chloropyrimidinyl) -tert-butyl
B142 (a, b, c, and d) -4-(5-chloropyrimidinyl) -iso-butyl
B143 (a, b, c, and d) -4-(5-chloropyrimidinyl) -sec-butyl
B144 (a, b, c, and d) -4-(5-chloropyrimidinyl) -cyclohexyl
B145 (a, b, c, and d) -4-(5-chloropyrimidinyl) -tert-butoxy
B146 (a, b, c, and d) -4-(5-chloropyrimidinyl) -iso-propoxy
B147 (a, b, c, and d) -4-(5-chloropyrimidinyl) —CF3
B148 (a, b, c, and d) -4-(5-chloropyrimidinyl) —OCF3
B149 (a, b, c, and d) -4-(5-chloropyrimidinyl) —Cl
B150 (a, b, c, and d) -4-(5-chloropyrimidinyl) —Br
B151 (a, b, c, and d) -4-(5-chloropyrimidinyl) —I
B152 (a, b, c, and d) -4-(5-chloropyrimidinyl) -n-butyl
B153 (a, b, c, and d) -4-(5-chloropyrimidinyl) -n-propyl
B154 (a, b, c, and d) -4-(5-chloropyrimidinyl) -iso-propyl
B155 (a, b, c, and d) -4-(5-methylpyrimidinyl) -tert-butyl
B156 (a, b, c, and d) -4-(5-methylpyrimidinyl) -iso-butyl
B157 (a, b, c, and d) -4-(5-methylpyrimidinyl) -sec-butyl
B158 (a, b, c, and d) -4-(5-methylpyrimidinyl) -cyclohexyl
B159 (a, b, c, and d) -4-(5-methylpyrimidinyl) -tert-butoxy
B160 (a, b, c, and d) -4-(5-methylpyrimidinyl) -iso-propoxy
B161 (a, b, c, and d) -4-(5-methylpyrimidinyl) —CF3
B162 (a, b, c, and d) -4-(5-methylpyrimidinyl) —OCF3
B163 (a, b, c, and d) -4-(5-methylpyrimidinyl) —Cl
B164 (a, b, c, and d) -4-(5-methylpyrimidinyl) —Br
B165 (a, b, c, and d) -4-(5-methylpyrimidinyl) —I
B166 (a, b, c, and d) -4-(5-methylpyrimidinyl) -n-butyl
B167 (a, b, c, and d) -4-(5-methylpyrimidinyl) -n-propyl
B168 (a, b, c, and d) -4-(5-methylpyrimidinyl) -iso-propyl
B169 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -tert-butyl
B170 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -iso-butyl
B171 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -sec-butyl
B172 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -cyclohexyl
B173 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -tert-butoxy
B174 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -iso-propoxy
B175 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —CF3
B176 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —OCF3
B177 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —Cl
B178 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —Br
B179 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —I
B180 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -n-butyl
B181 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -n-propyl
B182 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -iso-propyl
B183 (a, b, c, and d) -2-(3-chloropyrazinyl) -tert-butyl
B184 (a, b, c, and d) -2-(3-chloropyrazinyl) -iso-butyl
B185 (a, b, c, and d) -2-(3-chloropyrazinyl) -sec-butyl
B186 (a, b, c, and d) -2-(3-chloropyrazinyl) -cyclohexyl
B187 (a, b, c, and d) -2-(3-chloropyrazinyl) -tert-butoxy
B188 (a, b, c, and d) -2-(3-chloropyrazinyl) -iso-propoxy
B189 (a, b, c, and d) -2-(3-chloropyrazinyl) —CF3
B190 (a, b, c, and d) -2-(3-chloropyrazinyl) —OCF3
B191 (a, b, c, and d) -2-(3-chloropyrazinyl) —Cl
B192 (a, b, c, and d) -2-(3-chloropyrazinyl) —Br
B193 (a, b, c, and d) -2-(3-chloropyrazinyl) —I
B194 (a, b, c, and d) -2-(3-chloropyrazinyl) -n-butyl
B195 (a, b, c, and d) -2-(3-chloropyrazinyl) -n-propyl
B196 (a, b, c, and d) -2-(3-chloropyrazinyl) -iso-propyl
B197 (a, b, c, and d) -2-(3-methylpyrazinyl) -tert-butyl
B198 (a, b, c, and d) -2-(3-methylpyrazinyl) -iso-butyl
B199 (a, b, c, and d) -2-(3-methylpyrazinyl) -sec-butyl
B200 (a, b, c, and d) -2-(3-methylpyrazinyl) -cyclohexyl
B201 (a, b, c, and d) -2-(3-methylpyrazinyl) -tert-butoxy
B202 (a, b, c, and d) -2-(3-methylpyrazinyl) -iso-propoxy
B203 (a, b, c, and d) -2-(3-methylpyrazinyl) —CF3
B204 (a, b, c, and d) -2-(3-methylpyrazinyl) —OCF3
B205 (a, b, c, and d) -2-(3-methylpyrazinyl) —Cl
B206 (a, b, c, and d) -2-(3-methylpyrazinyl) —Br
B207 (a, b, c, and d) -2-(3-methylpyrazinyl) —I
B208 (a, b, c, and d) -2-(3-methylpyrazinyl) -n-butyl
B209 (a, b, c, and d) -2-(3-methylpyrazinyl) -n-propyl
B210 (a, b, c, and d) -2-(3-methylpyrazinyl) -iso-propyl
B211 (a, b, c, and d) -2-(3-fluoropyrazinyl) -tert-butyl
B212 (a, b, c, and d) -2-(3-fluoropyrazinyl) -iso-butyl
B213 (a, b, c, and d) -2-(3-fluoropyrazinyl) -sec-butyl
B214 (a, b, c, and d) -2-(3-fluoropyrazinyl) -cyclohexyl
B215 (a, b, c, and d) -2-(3-fluoropyrazinyl) -tert-butoxy
B216 (a, b, c, and d) -2-(3-fluoropyrazinyl) -iso-propoxy
B217 (a, b, c, and d) -2-(3-fluoropyrazinyl) —CF3
B218 (a, b, c, and d) -2-(3-fluoropyrazinyl) —OCF3
B219 (a, b, c, and d) -2-(3-fluoropyrazinyl) —Cl
B220 (a, b, c, and d) -2-(3-fluoropyrazinyl) —Br
B221 (a, b, c, and d) -2-(3-fluoropyrazinyl) —I
B222 (a, b, c, and d) -2-(3-fluoropyrazinyl) -n-butyl
B223 (a, b, c, and d) -2-(3-fluoropyrazinyl) -n-propyl
B224 (a, b, c, and d) -2-(3-fluoropyrazinyl) -iso-propyl
B225 (a, b, c, and d) -3-(4-chloropyridazinyl) -tert-butyl
B226 (a, b, c, and d) -3-(4-chloropyridazinyl) -iso-butyl
B227 (a, b, c, and d) -3-(4-chloropyridazinyl) -sec-butyl
B228 (a, b, c, and d) -3-(4-chloropyridazinyl) -cyclohexyl
B229 (a, b, c, and d) -3-(4-chloropyridazinyl) -tert-butoxy
B230 (a, b, c, and d) -3-(4-chloropyridazinyl) -iso-propoxy
B231 (a, b, c, and d) -3-(4-chloropyridazinyl) —CF3
B232 (a, b, c, and d) -3-(4-chloropyridazinyl) —OCF3
B233 (a, b, c, and d) -3-(4-chloropyridazinyl) —Cl
B234 (a, b, c, and d) -3-(4-chloropyridazinyl) —Br
B235 (a, b, c, and d) -3-(4-chloropyridazinyl) —I
B236 (a, b, c, and d) -3-(4-chloropyridazinyl) -n-butyl
B237 (a, b, c, and d) -3-(4-chloropyridazinyl) -n-propyl
B238 (a, b, c, and d) -3-(4-chloropyridazinyl) -iso-propyl
B239 (a, b, c, and d) -3-(4-methylpyridazinyl) -tert-butyl
B240 (a, b, c, and d) -3-(4-methylpyridazinyl) -iso-butyl
B241 (a, b, c, and d) -3-(4-methylpyridazinyl) -sec-butyl
B242 (a, b, c, and d) -3-(4-methylpyridazinyl) -cyclohexyl
B243 (a, b, c, and d) -3-(4-methylpyridazinyl) -tert-butoxy
B244 (a, b, c, and d) -3-(4-methylpyridazinyl) -iso-propoxy
B245 (a, b, c, and d) -3-(4-methylpyridazinyl) —CF3
B246 (a, b, c, and d) -3-(4-methylpyridazinyl) —OCF3
B247 (a, b, c, and d) -3-(4-methylpyridazinyl) —Cl
B248 (a, b, c, and d) -3-(4-methylpyridazinyl) —Br
B249 (a, b, c, and d) -3-(4-methylpyridazinyl) —I
B250 (a, b, c, and d) -3-(4-methylpyridazinyl) -n-butyl
B251 (a, b, c, and d) -3-(4-methylpyridazinyl) -n-propyl
B252 (a, b, c, and d) -3-(4-methylpyridazinyl) -iso-propyl
B253 (a, b, c, and d) -3-(4-fluoropyridazinyl) -tert-butyl
B254 (a, b, c, and d) -3-(4-fluoropyridazinyl) -iso-butyl
B255 (a, b, c, and d) -3-(4-fluoropyridazinyl) -sec-butyl
B256 (a, b, c, and d) -3-(4-fluoropyridazinyl) -cyclohexyl
B257 (a, b, c, and d) -3-(4-fluoropyridazinyl) -tert-butoxy
B258 (a, b, c, and d) -3-(4-fluoropyridazinyl) -iso-propoxy
B259 (a, b, c, and d) -3-(4-fluoropyridazinyl) —CF3
B260 (a, b, c, and d) -3-(4-fluoropyridazinyl) —OCF3
B261 (a, b, c, and d) -3-(4-fluoropyridazinyl) —Cl
B262 (a, b, c, and d) -3-(4-fluoropyridazinyl) —Br
B263 (a, b, c, and d) -3-(4-fluoropyridazinyl) —I
B264 (a, b, c, and d) -3-(4-fluoropyridazinyl) -n-butyl
B265 (a, b, c, and d) -3-(4-fluoropyridazinyl) -n-propyl
B266 (a, b, c, and d) -3-(4-fluoropyridazinyl) -iso-propyl
B267 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -tert-butyl
B268 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -iso-butyl
B269 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -sec-butyl
B270 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -cyclohexyl
B271 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -tert-butoxy
B272 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -iso-propoxy
B273 (a, b, c, and d) -5-(4-chlorothiadiazolyl) —CF3
B274 (a, b, c, and d) -5-(4-chlorothiadiazolyl) —OCF3
B275 (a, b, c, and d) -5-(4-chlorothiadiazolyl) —Cl
B276 (a, b, c, and d) -5-(4-chlorothiadiazolyl) —Br
B277 (a, b, c, and d) -5-(4-chlorothiadiazolyl) —I
B278 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -n-butyl
B279 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -n-propyl
B280 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -iso-propyl
B281 (a, b, c, and d) -5-(4-methylthiadiazolyl) -tert-butyl
B282 (a, b, c, and d) -5-(4-methylthiadiazolyl) -iso-butyl
B283 (a, b, c, and d) -5-(4-methylthiadiazolyl) -sec-butyl
B284 (a, b, c, and d) -5-(4-methylthiadiazolyl) -cyclohexyl
B285 (a, b, c, and d) -5-(4-methylthiadiazolyl) -tert-butoxy
B286 (a, b, c, and d) -5-(4-methylthiadiazolyl) -iso-propoxy
B287 (a, b, c, and d) -5-(4-methylthiadiazolyl) —CF3
B288 (a, b, c, and d) -5-(4-methylthiadiazolyl) —OCF3
B289 (a, b, c, and d) -5-(4-methylthiadiazolyl) —Cl
B290 (a, b, c, and d) -5-(4-methylthiadiazolyl) —Br
B291 (a, b, c, and d) -5-(4-methylthiadiazolyl) —I
B292 (a, b, c, and d) -5-(4-methylthiadiazolyl) -n-butyl
B293 (a, b, c, and d) -5-(4-methylthiadiazolyl) -n-propyl
B294 (a, b, c, and d) -5-(4-methylthiadiazolyl) -iso-propyl
B295 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -tert-butyl
B296 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -iso-butyl
B297 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -sec-butyl
B298 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -cyclohexyl
B299 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -tert-butoxy
B300 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -iso-propoxy
B301 (a, b, c, and d) -5-(4-fluorothiadiazolyl) —CF3
B302 (a, b, c, and d) -5-(4-fluorothiadiazolyl) —OCF3
B303 (a, b, c, and d) -5-(4-fluorothiadiazolyl) —Cl
B304 (a, b, c, and d) -5-(4-fluorothiadiazolyl) —Br
B305 (a, b, c, and d) -5-(4-fluorothiadiazolyl) —I
B306 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -n-butyl
B307 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -n-propyl
B308 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -iso-propyl
“a” means R3 is —H.
“b” means R3 is —CH3 and the Nitro(cyano)vinylpiperazine Compound is racemic.
“c” means R3 is —CH3 and the carbon atom to which R3 is attached is in the (R) configuration.
“d” means R3 is —CH3 and the carbon atom to which R3 is attached is in the (S) configuration.

TABLE 3
(V)
and pharmaceutically acceptable salts thereof, where:
Compound Ar1 R8a
C1 (a, b, c, and d) -2-(3-chloropyridyl) -tert-butyl
C2 (a, b, c, and d) -2-(3-chloropyridyl) -iso-butyl
C3 (a, b, c, and d) -2-(3-chloropyridyl) -sec-butyl
C4 (a, b, c, and d) -2-(3-chloropyridyl) -cyclohexyl
C5 (a, b, c, and d) -2-(3-chloropyridyl) -tert-butoxy
C6 (a, b, c, and d) -2-(3-chloropyridyl) -iso-propoxy
C7 (a, b, c, and d) -2-(3-chloropyridyl) —CF3
C8 (a, b, c, and d) -2-(3-chloropyridyl) —OCF3
C9 (a, b, c, and d) -2-(3-chloropyridyl) —Cl
C10 (a, b, c, and d) -2-(3-chloropyridyl) —Br
C11 (a, b, c, and d) -2-(3-chloropyridyl) —I
C12 (a, b, c, and d) -2-(3-chloropyridyl) -n-butyl
C13 (a, b, c, and d) -2-(3-chloropyridyl) -n-propyl
C14 (a, b, c, and d) -2-(3-chloropyridyl) -iso-propyl
C15 (a, b, c, and d) -2-(3-fluoropyridyl) -tert-butyl
C16 (a, b, c, and d) -2-(3-fluoropyridyl) -iso-butyl
C17 (a, b, c, and d) -2-(3-fluoropyridyl) -sec-butyl
C18 (a, b, c, and d) -2-(3-fluoropyridyl) -cyclohexyl
C19 (a, b, c, and d) -2-(3-fluoropyridyl) -tert-butoxy
C20 (a, b, c, and d) -2-(3-fluoropyridyl) -iso-propoxy
C21 (a, b, c, and d) -2-(3-fluoropyridyl) —CF3
C22 (a, b, c, and d) -2-(3-fluoropyridyl) —OCF3
C23 (a, b, c, and d) -2-(3-fluoropyridyl) —Cl
C24 (a, b, c, and d) -2-(3-fluoropyridyl) —Br
C25 (a, b, c, and d) -2-(3-fluoropyridyl) —I
C26 (a, b, c, and d) -2-(3-fluoropyridyl) -n-butyl
C27 (a, b, c, and d) -2-(3-fluoropyridyl) -n-propyl
C28 (a, b, c, and d) -2-(3-fluoropyridyl) -iso-propyl
C29 (a, b, c, and d) -2-(3-methylpyridyl) -tert-butyl
C30 (a, b, c, and d) -2-(3-methylpyridyl) -iso-butyl
C31 (a, b, c, and d) -2-(3-methylpyridyl) -sec-butyl
C32 (a, b, c, and d) -2-(3-methylpyridyl) -cyclohexyl
C33 (a, b, c, and d) -2-(3-methylpyridyl) -tert-butoxy
C34 (a, b, c, and d) -2-(3-methylpyridyl) -iso-propoxy
C35 (a, b, c, and d) -2-(3-methylpyridyl) —CF3
C36 (a, b, c, and d) -2-(3-methylpyridyl) —OCF3
C37 (a, b, c, and d) -2-(3-methylpyridyl) —Cl
C38 (a, b, c, and d) -2-(3-methylpyridyl) —Br
C39 (a, b, c, and d) -2-(3-methylpyridyl) —I
C40 (a, b, c, and d) -2-(3-methylpyridyl) -n-butyl
C41 (a, b, c, and d) -2-(3-methylpyridyl) -n-propyl
C42 (a, b, c, and d) -2-(3-methylpyridyl) -iso-propyl
C43 (a, b, c, and d) -2-(3-CF3-pyridyl) -tert-butyl
C44 (a, b, c, and d) -2-(3-CF3-pyridyl) -iso-butyl
C45 (a, b, c, and d) -2-(3-CF3-pyridyl) -sec-butyl
C46 (a, b, c, and d) -2-(3-CF3-pyridyl) -cyclohexyl
C47 (a, b, c, and d) -2-(3-CF3-pyridyl) -tert-butoxy
C48 (a, b, c, and d) -2-(3-CF3-pyridyl) -iso-propoxy
C49 (a, b, c, and d) -2-(3-CF3-pyridyl) —CF3
C50 (a, b, c, and d) -2-(3-CF3-pyridyl) —OCF3
C51 (a, b, c, and d) -2-(3-CF3-pyridyl) —Cl
C52 (a, b, c, and d) -2-(3-CF3-pyridyl) —Br
C53 (a, b, c, and d) -2-(3-CF3-pyridyl) —I
C54 (a, b, c, and d) -2-(3-CF3-pyridyl) -n-butyl
C55 (a, b, c, and d) -2-(3-CF3-pyridyl) -n-propyl
C56 (a, b, c, and d) -2-(3-CF3-pyridyl) -iso-propyl
C57 (a, b, c, and d) -2-(3-CHF2-pyridyl) -tert-butyl
C58 (a, b, c, and d) -2-(3-CHF2-pyridyl) -iso-butyl
C59 (a, b, c, and d) -2-(3-CHF2-pyridyl) -sec-butyl
C60 (a, b, c, and d) -2-(3-CHF2-pyridyl) -cyclohexyl
C61 (a, b, c, and d) -2-(3-CHF2-pyridyl) -tert-butoxy
C62 (a, b, c, and d) -2-(3-CHF2-pyridyl) -iso-propoxy
C63 (a, b, c, and d) -2-(3-CHF2-pyridyl) —CF3
C64 (a, b, c, and d) -2-(3-CHF2-pyridyl) —OCF3
C65 (a, b, c, and d) -2-(3-CHF2-pyridyl) —Cl
C66 (a, b, c, and d) -2-(3-CHF2-pyridyl) —Br
C67 (a, b, c, and d) -2-(3-CHF2-pyridyl) —I
C68 (a, b, c, and d) -2-(3-CHF2-pyridyl) -n-butyl
C69 (a, b, c, and d) -2-(3-CHF2-pyridyl) -n-propyl
C70 (a, b, c, and d) -2-(3-CHF2-pyridyl) -iso-propyl
C71 (a, b, c, and d) -2-(3-hydroxypyridyl) -tert-butyl
C72 (a, b, c, and d) -2-(3-hydroxypyridyl) -iso-butyl
C73 (a, b, c, and d) -2-(3-hydroxypyridyl) -sec-butyl
C74 (a, b, c, and d) -2-(3-hydroxypyridyl) -cyclohexyl
C75 (a, b, c, and d) -2-(3-hydroxypyridyl) -tert-butoxy
C76 (a, b, c, and d) -2-(3-hydroxypyridyl) -iso-propoxy
C77 (a, b, c, and d) -2-(3-hydroxypyridyl) —CF3
C78 (a, b, c, and d) -2-(3-hydroxypyridyl) —OCF3
C79 (a, b, c, and d) -2-(3-hydroxypyridyl) —Cl
C80 (a, b, c, and d) -2-(3-hydroxypyridyl) —Br
C81 (a, b, c, and d) -2-(3-hydroxypyridyl) —I
C82 (a, b, c, and d) -2-(3-hydroxypyridyl) -n-butyl
C83 (a, b, c, and d) -2-(3-hydroxypyridyl) -n-propyl
C84 (a, b, c, and d) -2-(3-hydroxypyridyl) -iso-propyl
C85 (a, b, c, and d) -2-(3-nitropyridyl) -tert-butyl
C86 (a, b, c, and d) -2-(3-nitropyridyl) -iso-butyl
C87 (a, b, c, and d) -2-(3-nitropyridyl) -sec-butyl
C88 (a, b, c, and d) -2-(3-nitropyridyl) -cyclohexyl
C89 (a, b, c, and d) -2-(3-nitropyridyl) -tert-butoxy
C90 (a, b, c, and d) -2-(3-nitropyridyl) -iso-propoxy
C91 (a, b, c, and d) -2-(3-nitropyridyl) —CF3
C92 (a, b, c, and d) -2-(3-nitropyridyl) —OCF3
C93 (a, b, c, and d) -2-(3-nitropyridyl) —Cl
C94 (a, b, c, and d) -2-(3-nitropyridyl) —Br
C95 (a, b, c, and d) -2-(3-nitropyridyl) —I
C96 (a, b, c, and d) -2-(3-nitropyridyl) -n-butyl
C97 (a, b, c, and d) -2-(3-nitropyridyl) -n-propyl
C98 (a, b, c, and d) -2-(3-nitropyridyl) -iso-propyl
C99 (a, b, c, and d) -2-(3-cyanopyridyl) -tert-butyl
C100 (a, b, c, and d) -2-(3-cyanopyridyl) -iso-butyl
C101 (a, b, c, and d) -2-(3-cyanopyridyl) -sec-butyl
C102 (a, b, c, and d) -2-(3-cyanopyridyl) -cyclohexyl
C103 (a, b, c, and d) -2-(3-cyanopyridyl) -tert-butoxy
C104 (a, b, c, and d) -2-(3-cyanopyridyl) -iso-propoxy
C105 (a, b, c, and d) -2-(3-cyanopyridyl) —CF3
C106 (a, b, c, and d) -2-(3-cyanopyridyl) —OCF3
C107 (a, b, c, and d) -2-(3-cyanopyridyl) —Cl
C108 (a, b, c, and d) -2-(3-cyanopyridyl) —Br
C109 (a, b, c, and d) -2-(3-cyanopyridyl) —I
C110 (a, b, c, and d) -2-(3-cyanopyridyl) -n-butyl
C111 (a, b, c, and d) -2-(3-cyanopyridyl) -n-propyl
C112 (a, b, c, and d) -2-(3-cyanopyridyl) -isopropyl
C113 (a, b, c, and d) -2-(3-bromopyridyl) -tert-butyl
C114 (a, b, c, and d) -2-(3-bromopyridyl) -iso-butyl
C115 (a, b, c, and d) -2-(3-bromopyridyl) -sec-butyl
C116 (a, b, c, and d) -2-(3-bromopyridyl) -cyclohexyl
C117 (a, b, c, and d) -2-(3-bromopyridyl) -tert-butoxy
C118 (a, b, c, and d) -2-(3-bromopyridyl) -iso-propoxy
C119 (a, b, c, and d) -2-(3-bromopyridyl) —CF3
C120 (a, b, c, and d) -2-(3-bromopyridyl) —OCF3
C121 (a, b, c, and d) -2-(3-bromopyridyl) —Cl
C122 (a, b, c, and d) -2-(3-bromopyridyl) —Br
C123 (a, b, c, and d) -2-(3-bromopyridyl) —I
C124 (a, b, c, and d) -2-(3-bromopyridyl) -n-butyl
C125 (a, b, c, and d) -2-(3-bromopyridyl) -n-propyl
C126 (a, b, c, and d) -2-(3-bromopyridyl) -iso-propyl
C127 (a, b, c, and d) -2-(3-iodopyridyl) -tert-butyl
C128 (a, b, c, and d) -2-(3-iodopyridyl) -iso-butyl
C129 (a, b, c, and d) -2-(3-iodopyridyl) -sec-butyl
C130 (a, b, c, and d) -2-(3-iodopyridyl) -cyclohexyl
C131 (a, b, c, and d) -2-(3-iodopyridyl) -tert-butoxy
C132 (a, b, c, and d) -2-(3-iodopyridyl) -iso-propoxy
C133 (a, b, c, and d) -2-(3-iodopyridyl) —CF3
C134 (a, b, c, and d) -2-(3-iodopyridyl) —OCF3
C135 (a, b, c, and d) -2-(3-iodopyridyl) —Cl
C136 (a, b, c, and d) -2-(3-iodopyridyl) —Br
C137 (a, b, c, and d) -2-(3-iodopyridyl) —I
C138 (a, b, c, and d) -2-(3-iodopyridyl) -n-butyl
C139 (a, b, c, and d) -2-(3-iodopyridyl) -n-propyl
C140 (a, b, c, and d) -2-(3-iodopyridyl) -iso-propyl
C141 (a, b, c, and d) -4-(5-chloropyrimidinyl) -tert-butyl
C142 (a, b, c, and d) -4-(5-chloropyrimidinyl) -iso-butyl
C143 (a, b, c, and d) -4-(5-chloropyrimidinyl) -sec-butyl
C144 (a, b, c, and d) -4-(5-chloropyrimidinyl) -cyclohexyl
C145 (a, b, c, and d) -4-(5-chloropyrimidinyl) -tert-butoxy
C146 (a, b, c, and d) -4-(5-chloropyrimidinyl) -iso-propoxy
C147 (a, b, c, and d) -4-(5-chloropyrimidinyl) —CF3
C148 (a, b, c, and d) -4-(5-chloropyrimidinyl) —OCF3
C149 (a, b, c, and d) -4-(5-chloropyrimidinyl) —Cl
C150 (a, b, c, and d) -4-(5-chloropyrimidinyl) —Br
C151 (a, b, c, and d) -4-(5-chloropyrimidinyl) —I
C152 (a, b, c, and d) -4-(5-chloropyrimidinyl) -n-butyl
C153 (a, b, c, and d) -4-(5-chloropyrimidinyl) -n-propyl
C154 (a, b, c, and d) -4-(5-chloropyrimidinyl) -iso-propyl
C155 (a, b, c, and d) -4-(5-methylpyrimidinyl) -tert-butyl
C156 (a, b, c, and d) -4-(5-methylpyrimidinyl) -iso-butyl
C157 (a, b, c, and d) -4-(5-methylpyrimidinyl) -sec-butyl
C158 (a, b, c, and d) -4-(5-methylpyrimidinyl) -cyclohexyl
C159 (a, b, c, and d) -4-(5-methylpyrimidinyl) -tert-butoxy
C160 (a, b, c, and d) -4-(5-methylpyrimidinyl) -iso-propoxy
C161 (a, b, c, and d) -4-(5-methylpyrimidinyl) —CF3
C162 (a, b, c, and d) -4-(5-methylpyrimidinyl) —OCF3
C163 (a, b, c, and d) -4-(5-methylpyrimidinyl) —Cl
C164 (a, b, c, and d) -4-(5-methylpyrimidinyl) —Br
C165 (a, b, c, and d) -4-(5-methylpyrimidinyl) —I
C166 (a, b, c, and d) -4-(5-methylpyrimidinyl) -n-butyl
C167 (a, b, c, and d) -4-(5-methylpyrimidinyl) -n-propyl
C168 (a, b, c, and d) -4-(5-methylpyrimidinyl) -iso-propyl
C169 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -tert-butyl
C170 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -iso-butyl
C171 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -sec-butyl
C172 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -cyclohexyl
C173 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -tert-butoxy
C174 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -iso-propoxy
C175 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —CF3
C176 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —OCF3
C177 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —Cl
C178 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —Br
C179 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —I
C180 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -n-butyl
C181 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -n-propyl
C182 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -iso-propyl
C183 (a, b, c, and d) -2-(3-chloropyrazinyl) -tert-butyl
C184 (a, b, c, and d) -2-(3-chloropyrazinyl) -iso-butyl
C185 (a, b, c, and d) -2-(3-chloropyrazinyl) -sec-butyl
C186 (a, b, c, and d) -2-(3-chloropyrazinyl) -cyclohexyl
C187 (a, b, c, and d) -2-(3-chloropyrazinyl) -tert-butoxy
C188 (a, b, c, and d) -2-(3-chloropyrazinyl) -iso-propoxy
C189 (a, b, c, and d) -2-(3-chloropyrazinyl) —CF3
C190 (a, b, c, and d) -2-(3-chloropyrazinyl) —OCF3
C191 (a, b, c, and d) -2-(3-chloropyrazinyl) —Cl
C192 (a, b, c, and d) -2-(3-chloropyrazinyl) —Br
C193 (a, b, c, and d) -2-(3-chloropyrazinyl) —I
C194 (a, b, c, and d) -2-(3-chloropyrazinyl) -n-butyl
C195 (a, b, c, and d) -2-(3-chloropyrazinyl) -n-propyl
C196 (a, b, c, and d) -2-(3-chloropyrazinyl) -iso-propyl
C197 (a, b, c, and d) -2-(3-methylpyrazinyl) -tert-butyl
C198 (a, b, c, and d) -2-(3-methylpyrazinyl) -iso-butyl
C199 (a, b, c, and d) -2-(3-methylpyrazinyl) -sec-butyl
C200 (a, b, c, and d) -2-(3-methylpyrazinyl) -cyclohexyl
C201 (a, b, c, and d) -2-(3-methylpyrazinyl) -tert-butoxy
C202 (a, b, c, and d) -2-(3-methylpyrazinyl) -iso-propoxy
C203 (a, b, c, and d) -2-(3-methylpyrazinyl) —CF3
C204 (a, b, c, and d) -2-(3-methylpyrazinyl) —OCF3
C205 (a, b, c, and d) -2-(3-methylpyrazinyl) —Cl
C206 (a, b, c, and d) -2-(3-methylpyrazinyl) —Br
C207 (a, b, c, and d) -2-(3-methylpyrazinyl) —I
C208 (a, b, c, and d) -2-(3-methylpyrazinyl) -n-butyl
C209 (a, b, c, and d) -2-(3-methylpyrazinyl) -n-propyl
C210 (a, b, c, and d) -2-(3-methylpyrazinyl) -iso-propyl
C211 (a, b, c, and d) -2-(3-fluoropyrazinyl) -tert-butyl
C212 (a, b, c, and d) -2-(3-fluoropyrazinyl) -iso-butyl
C213 (a, b, c, and d) -2-(3-fluoropyrazinyl) -sec-butyl
C214 (a, b, c, and d) -2-(3-fluoropyrazinyl) -cyclohexyl
C215 (a, b, c, and d) -2-(3-fluoropyrazinyl) -tert-butoxy
C216 (a, b, c, and d) -2-(3-fluoropyrazinyl) -iso-propoxy
C217 (a, b, c, and d) -2-(3-fluoropyrazinyl) —CF3
C218 (a, b, c, and d) -2-(3-fluoropyrazinyl) —OCF3
C219 (a, b, c, and d) -2-(3-fluoropyrazinyl) —Cl
C220 (a, b, c, and d) -2-(3-fluoropyrazinyl) —Br
C221 (a, b, c, and d) -2-(3-fluoropyrazinyl) —I
C222 (a, b, c, and d) -2-(3-fluoropyrazinyl) -n-butyl
C223 (a, b, c, and d) -2-(3-fluoropyrazinyl) -n-propyl
C224 (a, b, c, and d) -2-(3-fluoropyrazinyl) -iso-propyl
C225 (a, b, c, and d) -3-(4-chloropyridazinyl) -tert-butyl
C226 (a, b, c, and d) -3-(4-chloropyridazinyl) -iso-butyl
C227 (a, b, c, and d) -3-(4-chloropyridazinyl) -sec-butyl
C228 (a, b, c, and d) -3-(4-chloropyridazinyl) -cyclohexyl
C229 (a, b, c, and d) -3-(4-chloropyridazinyl) -tert-butoxy
C230 (a, b, c, and d) -3-(4-chloropyridazinyl) -iso-propoxy
C231 (a, b, c, and d) -3-(4-chloropyridazinyl) —CF3
C232 (a, b, c, and d) -3-(4-chloropyridazinyl) —OCF3
C233 (a, b, c, and d) -3-(4-chloropyridazinyl) —Cl
C234 (a, b, c, and d) -3-(4-chloropyridazinyl) —Br
C235 (a, b, c, and d) -3-(4-chloropyridazinyl) —I
C236 (a, b, c, and d) -3-(4-chloropyridazinyl) -n-butyl
C237 (a, b, c, and d) -3-(4-chloropyridazinyl) -n-propyl
C238 (a, b, c, and d) -3-(4-chloropyridazinyl) -iso-propyl
C239 (a, b, c, and d) -3-(4-methylpyridazinyl) -tert-butyl
C240 (a, b, c, and d) -3-(4-methylpyridazinyl) -iso-butyl
C241 (a, b, c, and d) -3-(4-methylpyridazinyl) -sec-butyl
C242 (a, b, c, and d) -3-(4-methylpyridazinyl) -cyclohexyl
C243 (a, b, c, and d) -3-(4-methylpyridazinyl) -tert-butoxy
C244 (a, b, c, and d) -3-(4-methylpyridazinyl) -iso-propoxy
C245 (a, b, c, and d) -3-(4-methylpyridazinyl) —CF3
C246 (a, b, c, and d) -3-(4-methylpyridazinyl) —OCF3
C247 (a, b, c, and d) -3-(4-methylpyridazinyl) —Cl
C248 (a, b, c, and d) -3-(4-methylpyridazinyl) —Br
C249 (a, b, c, and d) -3-(4-methylpyridazinyl) —I
C250 (a, b, c, and d) -3-(4-methylpyridazinyl) -n-butyl
C251 (a, b, c, and d) -3-(4-methylpyridazinyl) -n-propyl
C252 (a, b, c, and d) -3-(4-methylpyridazinyl) -iso-propyl
C253 (a, b, c, and d) -3-(4-fluoropyridazinyl) -tert-butyl
C254 (a, b, c, and d) -3-(4-fluoropyridazinyl) -iso-butyl
C255 (a, b, c, and d) -3-(4-fluoropyridazinyl) -sec-butyl
C256 (a, b, c, and d) -3-(4-fluoropyridazinyl) -cyclohexyl
C257 (a, b, c, and d) -3-(4-fluoropyridazinyl) -tert-butoxy
C258 (a, b, c, and d) -3-(4-fluoropyridazinyl) -iso-propoxy
C259 (a, b, c, and d) -3-(4-fluoropyridazinyl) —CF3
C260 (a, b, c, and d) -3-(4-fluoropyridazinyl) —OCF3
C261 (a, b, c, and d) -3-(4-fluoropyridazinyl) —Cl
C262 (a, b, c, and d) -3-(4-fluoropyridazinyl) —Br
C263 (a, b, c, and d) -3-(4-fluoropyridazinyl) —I
C264 (a, b, c, and d) -3-(4-fluoropyridazinyl) -n-butyl
C265 (a, b, c, and d) -3-(4-fluoropyridazinyl) -n-propyl
C266 (a, b, c, and d) -3-(4-fluoropyridazinyl) -iso-propyl
C267 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -tert-butyl
C268 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -iso-butyl
C269 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -sec-butyl
C270 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -cyclohexyl
C271 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -tert-butoxy
C272 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -iso-propoxy
C273 (a, b, c, and d) -5-(4-chlorothiadiazolyl) —CF3
C274 (a, b, c, and d) -5-(4-chlorothiadiazolyl) —OCF3
C275 (a, b, c, and d) -5-(4-chlorothiadiazolyl) —Cl
C276 (a, b, c, and d) -5-(4-chlorothiadiazolyl) —Br
C277 (a, b, c, and d) -5-(4-chlorothiadiazolyl) —I
C278 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -n-butyl
C279 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -n-propyl
C280 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -iso-propyl
C281 (a, b, c, and d) -5-(4-methylthiadiazolyl) -tert-butyl
C282 (a, b, c, and d) -5-(4-methylthiadiazolyl) -iso-butyl
C283 (a, b, c, and d) -5-(4-methylthiadiazolyl) -sec-butyl
C284 (a, b, c, and d) -5-(4-methylthiadiazolyl) -cyclohexyl
C285 (a, b, c, and d) -5-(4-methylthiadiazolyl) -tert-butoxy
C286 (a, b, c, and d) -5-(4-methylthiadiazolyl) -iso-propoxy
C287 (a, b, c, and d) -5-(4-methylthiadiazolyl) —CF3
C288 (a, b, c, and d) -5-(4-methylthiadiazolyl) —OCF3
C289 (a, b, c, and d) -5-(4-methylthiadiazolyl) —Cl
C290 (a, b, c, and d) -5-(4-methylthiadiazolyl) —Br
C291 (a, b, c, and d) -5-(4-methylthiadiazolyl) —I
C292 (a, b, c, and d) -5-(4-methylthiadiazolyl) -n-butyl
C293 (a, b, c, and d) -5-(4-methylthiadiazolyl) -n-propyl
C294 (a, b, c, and d) -5-(4-methylthiadiazolyl) -iso-propyl
C295 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -tert-butyl
C296 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -iso-butyl
C297 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -sec-butyl
C298 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -cyclohexyl
C299 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -tert-butoxy
C300 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -iso-propoxy
C301 (a, b, c, and d) -5-(4-fluorothiadiazolyl) —CF3
C302 (a, b, c, and d) -5-(4-fluorothiadiazolyl) —OCF3
C303 (a, b, c, and d) -5-(4-fluorothiadiazolyl) —Cl
C304 (a, b, c, and d) -5-(4-fluorothiadiazolyl) —Br
C305 (a, b, c, and d) -5-(4-fluorothiadiazolyl) —I
C306 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -n-butyl
C307 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -n-propyl
C308 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -iso-propyl
“a” means R3 is —H.
“b” means R3 is —CH3 and the Nitro(cyano)vinylpiperazine Compound is racemic.
“c” means R3 is —CH3 and the carbon atom to which R3 is attached is in the (R) configuration.
“d” means R3 is —CH3 and the carbon atom to which R3 is attached is in the (S) configuration.

TABLE 4
(VI)
and pharmaceutically acceptable salts thereof, where:
Compound Ar1 R8a
D1 (a, b, c, and d) -2-(3-chloropyridyl) -tert-butyl
D2 (a, b, c, and d) -2-(3-chloropyridyl) -iso-butyl
D3 (a, b, c, and d) -2-(3-chloropyridyl) -sec-butyl
D4 (a, b, c, and d) -2-(3-chloropyridyl) -cyclohexyl
D5 (a, b, c, and d) -2-(3-chloropyridyl) -tert-butoxy
D6 (a, b, c, and d) -2-(3-chloropyridyl) -iso-propoxy
D7 (a, b, c, and d) -2-(3-chloropyridyl) —CF3
D8 (a, b, c, and d) -2-(3-chloropyridyl) —OCF3
D9 (a, b, c, and d) -2-(3-chloropyridyl) —Cl
D10 (a, b, c, and d) -2-(3-chloropyridyl) —Br
D11 (a, b, c, and d) -2-(3-chloropyridyl) —I
D12 (a, b, c, and d) -2-(3-chloropyridyl) -n-butyl
D13 (a, b, c, and d) -2-(3-chloropyridyl) -n-propyl
D14 (a, b, c, and d) -2-(3-chloropyridyl) -iso-propyl
D15 (a, b, c, and d) -2-(3-fluoropyridyl) -tert-butyl
D16 (a, b, c, and d) -2-(3-fluoropyridyl) -iso-butyl
D17 (a, b, c, and d) -2-(3-fluoropyridyl) -sec-butyl
D18 (a, b, c, and d) -2-(3-fluoropyridyl) -cyclohexyl
D19 (a, b, c, and d) -2-(3-fluoropyridyl) -tert-butoxy
D20 (a, b, c, and d) -2-(3-fluoropyridyl) -iso-propoxy
D21 (a, b, c, and d) -2-(3-fluoropyridyl) —CF3
D22 (a, b, c, and d) -2-(3-fluoropyridyl) —OCF3
D23 (a, b, c, and d) -2-(3-fluoropyridyl) —Cl
D24 (a, b, c, and d) -2-(3-fluoropyridyl) —Br
D25 (a, b, c, and d) -2-(3-fluoropyridyl) —I
D26 (a, b, c, and d) -2-(3-fluoropyridyl) -n-butyl
D27 (a, b, c, and d) -2-(3-fluoropyridyl) -n-propyl
D28 (a, b, c, and d) -2-(3-fluoropyridyl) -iso-propyl
D29 (a, b, c, and d) -2-(3-methylpyridyl) -tert-butyl
D30 (a, b, c, and d) -2-(3-methylpyridyl) -iso-butyl
D31 (a, b, c, and d) -2-(3-methylpyridyl) -sec-butyl
D32 (a, b, c, and d) -2-(3-methylpyridyl) -cyclohexyl
D33 (a, b, c, and d) -2-(3-methylpyridyl) -tert-butoxy
D34 (a, b, c, and d) -2-(3-methylpyridyl) -iso-propoxy
D35 (a, b, c, and d) -2-(3-methylpyridyl) —CF3
D36 (a, b, c, and d) -2-(3-methylpyridyl) —OCF3
D37 (a, b, c, and d) -2-(3-methylpyridyl) —Cl
D38 (a, b, c, and d) -2-(3-methylpyridyl) —Br
D39 (a, b, c, and d) -2-(3-methylpyridyl) —I
D40 (a, b, c, and d) -2-(3-methylpyridyl) -n-butyl
D41 (a, b, c, and d) -2-(3-methylpyridyl) -n-propyl
D42 (a, b, c, and d) -2-(3-methylpyndyl) -iso-propyl
D43 (a, b, c, and d) -2-(3-CF3-pyridyl) -tert-butyl
D44 (a, b, c, and d) -2-(3-CF3-pyridyl) -iso-butyl
D45 (a, b, c, and d) -2-(3-CF3-pyridyl) -sec-butyl
D46 (a, b, c, and d) -2-(3-CF3-pyridyl) -cyclohexyl
D47 (a, b, c, and d) -2-(3-CF3-pyridyl) -tert-butoxy
D48 (a, b, c, and d) -2-(3-CF3-pyridyl) -iso-propoxy
D49 (a, b, c, and d) -2-(3-CF3-pyridyl) —CF3
D50 (a, b, c, and d) -2-(3-CF3-pyridyl) —OCF3
D51 (a, b, c, and d) -2-(3-CF3-pyridyl) —Cl
D52 (a, b, c, and d) -2-(3-CF3-pyridyl) —Br
D53 (a, b, c, and d) -2-(3-CF3-pyridyl) —I
D54 (a, b, c, and d) -2-(3-CF3-pyridyl) -n-butyl
D55 (a, b, c, and d) -2-(3-CF3-pyridyl) -n-propyl
D56 (a, b, c, and d) -2-(3-CF3-pyridyl) -iso-propyl
D57 (a, b, c, and d) -2-(3-CHF2-pyridyl) -tert-butyl
D58 (a, b, c, and d) -2-(3-CHF2-pyridyl) -iso-butyl
D59 (a, b, c, and d) -2-(3-CHF2-pyridyl) -sec-butyl
D60 (a, b, c, and d) -2-(3-CHF2-pyridyl) -cyclohexyl
D61 (a, b, c, and d) -2-(3-CHF2-pyridyl) -tert-butoxy
D62 (a, b, c, and d) -2-(3-CHF2-pyridyl) -iso-propoxy
D63 (a, b, c, and d) -2-(3-CHF2-pyridyl) —CF3
D64 (a, b, c, and d) -2-(3-CHF2-pyridyl) —OCF3
D65 (a, b, c, and d) -2-(3-CHF2-pyridyl) —Cl
D66 (a, b, c, and d) -2-(3-CHF2-pyridyl) —Br
D67 (a, b, c, and d) -2-(3-CHF2-pyridyl) —I
D68 (a, b, c, and d) -2-(3-CHF2-pyridyl) -n-butyl
D69 (a, b, c, and d) -2-(3-CHF2-pyridyl) -n-propyl
D70 (a, b, c, and d) -2-(3-CHF2-pyridyl) -iso-propyl
D71 (a, b, c, and d) -2-(3-hydroxypyridyl) -tert-butyl
D72 (a, b, c, and d) -2-(3-hydroxypyridyl) -iso-butyl
D73 (a, b, c, and d) -2-(3-hydroxypyridyl) -sec-butyl
D74 (a, b, c, and d) -2-(3-hydroxypyridyl) -cyclohexyl
D75 (a, b, c, and d) -2-(3-hydroxypyridyl) -tert-butoxy
D76 (a, b, c, and d) -2-(3-hydroxypyridyl) -iso-propoxy
D77 (a, b, c, and d) -2-(3-hydroxypyridyl) —CF3
D78 (a, b, c, and d) -2-(3-hydroxypyridyl) —OCF3
D79 (a, b, c, and d) -2-(3-hydroxypyridyl) —Cl
D80 (a, b, c, and d) -2-(3-hydroxypyridyl) —Br
D81 (a, b, c, and d) -2-(3-hydroxypyridyl) —I
D82 (a, b, c, and d) -2-(3-hydroxypyridyl) -n-butyl
D83 (a, b, c, and d) -2-(3-hydroxypyridyl) -n-propyl
D84 (a, b, c, and d) -2-(3-hydroxypyridyl) -iso-propyl
D85 (a, b, c, and d) -2-(3-nitropyridyl) -tert-butyl
D86 (a, b, c, and d) -2-(3-nitropyridyl) -iso-butyl
D87 (a, b, c, and d) -2-(3-nitropyridyl) -sec-butyl
D88 (a, b, c, and d) -2-(3-nitropyridyl) -cyclohexyl
D89 (a, b, c, and d) -2-(3-nitropyridyl) -tert-butoxy
D90 (a, b, c, and d) -2-(3-nitropyridyl) -iso-propoxy
D91 (a, b, c, and d) -2-(3-nitropyridyl) —CF3
D92 (a, b, c, and d) -2-(3-nitropyridyl) —OCF3
D93 (a, b, c, and d) -2-(3-nitropyridyl) —Cl
D94 (a, b, c, and d) -2-(3-nitropyridyl) —Br
D95 (a, b, c, and d) -2-(3-nitropyridyl) —I
D96 (a, b, c, and d) -2-(3-nitropyridyl) -n-butyl
D97 (a, b, c, and d) -2-(3-nitropyridyl) -n-propyl
D98 (a, b, c, and d) -2-(3-nitropyridyl) -iso-propyl
D99 (a, b, c, and d) -2-(3-cyanopyridyl) -tert-butyl
D100 (a, b, c, and d) -2-(3-cyanopyridyl) -iso-butyl
D101 (a, b, c, and d) -2-(3-cyanopyridyl) -sec-butyl
D102 (a, b, c, and d) -2-(3-cyanopyridyl) -cyclohexyl
D103 (a, b, c, and d) -2-(3-cyanopyridyl) -tert-butoxy
D104 (a, b, c, and d) -2-(3-cyanopyridyl) -iso-propoxy
D105 (a, b, c, and d) -2-(3-cyanopyridyl) —CF3
D106 (a, b, c, and d) -2-(3-cyanopyridyl) —OCF3
D107 (a, b, c, and d) -2-(3-cyanopyridyl) —Cl
D108 (a, b, c, and d) -2-(3-cyanopyridyl) —Br
D109 (a, b, c, and d) -2-(3-cyanopyridyl) —I
D110 (a, b, c, and d) -2-(3-cyanopyridyl) -n-butyl
D111 (a, b, c, and d) -2-(3-cyanopyridyl) -n-propyl
D112 (a, b, c, and d) -2-(3-cyanopyridyl) -isopropyl
D113 (a, b, c, and d) -2-(3-bromopyridyl) -tert-butyl
D114 (a, b, c, and d) -2-(3-bromopyridyl) -iso-butyl
D115 (a, b, c, and d) -2-(3-bromopyridyl) -sec-butyl
D116 (a, b, c, and d) -2-(3-bromopyridyl) -cyclohexyl
D117 (a, b, c, and d) -2-(3-bromopyridyl) -tert-butoxy
D118 (a, b, c, and d) -2-(3-bromopyridyl) -iso-propoxy
D119 (a, b, c, and d) -2-(3-bromopyridyl) —CF3
D120 (a, b, c, and d) -2-(3-bromopyridyl) —OCF3
D121 (a, b, c, and d) -2-(3-bromopyridyl) —Cl
D122 (a, b, c, and d) -2-(3-bromopyridyl) —Br
D123 (a, b, c, and d) -2-(3-bromopyridyl) —I
D124 (a, b, c, and d) -2-(3-bromopyridyl) -n-butyl
D125 (a, b, c, and d) -2-(3-bromopyridyl) -n-propyl
D126 (a, b, c, and d) -2-(3-bromopyridyl) -iso-propyl
D127 (a, b, c, and d) -2-(3-iodopyridyl) -tert-butyl
D128 (a, b, c, and d) -2-(3-iodopyridyl) -iso-butyl
D129 (a, b, c, and d) -2-(3-iodopyridyl) -sec-butyl
D130 (a, b, c, and d) -2-(3-iodopyridyl) -cyclohexyl
D131 (a, b, c, and d) -2-(3-iodopyridyl) -tert-butoxy
D132 (a, b, c, and d) -2-(3-iodopyridyl) -iso-propoxy
D133 (a, b, c, and d) -2-(3-iodopyridyl) —CF3
D134 (a, b, c, and d) -2-(3-iodopyridyl) —OCF3
D135 (a, b, c, and d) -2-(3-iodopyridyl) —Cl
D136 (a, b, c, and d) -2-(3-iodopyridyl) —Br
D137 (a, b, c, and d) -2-(3-iodopyridyl) —I
D138 (a, b, c, and d) -2-(3-iodopyridyl) -n-butyl
D139 (a, b, c, and d) -2-(3-iodopyridyl) -n-propyl
D140 (a, b, c, and d) -2-(3-iodopyridyl) -iso-propyl
D141 (a, b, c, and d) -4-(5-chloropyrimidinyl) -tert-butyl
D142 (a, b, c, and d) -4-(5-chloropyrimidinyl) -iso-butyl
D143 (a, b, c, and d) -4-(5-chloropyrimidinyl) -sec-butyl
D144 (a, b, c, and d) -4-(5-chloropyrimidinyl) -cyclohexyl
D145 (a, b, c, and d) -4-(5-chloropyrimidinyl) -tert-butoxy
D146 (a, b, c, and d) -4-(5-chloropyrimidinyl) -iso-propoxy
D147 (a, b, c, and d) -4-(5-chloropyrimidinyl) —CF3
D148 (a, b, c, and d) -4-(5-chloropyrimidinyl) —OCF3
D149 (a, b, c, and d) -4-(5-chloropyrimidinyl) —Cl
D150 (a, b, c, and d) -4-(5-chloropyrimidinyl) —Br
D151 (a, b, c, and d) -4-(5-chloropyrimidinyl) —I
D152 (a, b, c, and d) -4-(5-chloropyrimidinyl) -n-butyl
D153 (a, b, c, and d) -4-(5-chloropyrimidinyl) -n-propyl
D154 (a, b, c, and d) -4-(5-chloropyrimidinyl) -iso-propyl
D155 (a, b, c, and d) -4-(5-methylpyrimidinyl) -tert-butyl
D156 (a, b, c, and d) -4-(5-methylpyrimidinyl) -iso-butyl
D157 (a, b, c, and d) -4-(5-methylpyrimidinyl) -sec-butyl
D158 (a, b, c, and d) -4-(5-methylpyrimidinyl) -cyclohexyl
D159 (a, b, c, and d) -4-(5-methylpyrimidinyl) -tert-butoxy
D160 (a, b, c, and d) -4-(5-methylpyrimidinyl) -iso-propoxy
D161 (a, b, c, and d) -4-(5-methylpyrimidinyl) —CF3
D162 (a, b, c, and d) -4-(5-methylpyrimidinyl) —OCF3
D163 (a, b, c, and d) -4-(5-methylpyrimidinyl) —Cl
D164 (a, b, c, and d) -4-(5-methylpyrimidinyl) —Br
D165 (a, b, c, and d) -4-(5-methylpyrimidinyl) —I
D166 (a, b, c, and d) -4-(5-methylpyrimidinyl) -n-butyl
D167 (a, b, c, and d) -4-(5-methylpyrimidinyl) -n-propyl
D168 (a, b, c, and d) -4-(5-methylpyrimidinyl) -iso-propyl
D169 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -tert-butyl
D170 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -iso-butyl
D171 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -sec-butyl
D172 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -cyclohexyl
D173 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -tert-butoxy
D174 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -iso-propoxy
D175 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —CF3
D176 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —OCF3
D177 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —Cl
D178 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —Br
D179 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —I
D180 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -n-butyl
D181 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -n-propyl
D182 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -iso-propyl
D183 (a, b, c, and d) -2-(3-chloropyrazinyl) -tert-butyl
D184 (a, b, c, and d) -2-(3-chloropyrazinyl) -iso-butyl
D185 (a, b, c, and d) -2-(3-chloropyrazinyl) -sec-butyl
D186 (a, b, c, and d) -2-(3-chloropyrazinyl) -cyclohexyl
D187 (a, b, c, and d) -2-(3-chloropyrazinyl) -tert-butoxy
D188 (a, b, c, and d) -2-(3-chloropyrazinyl) -iso-propoxy
D189 (a, b, c, and d) -2-(3-chloropyrazinyl) —CF3
D190 (a, b, c, and d) -2-(3-chloropyrazinyl) —OCF3
D191 (a, b, c, and d) -2-(3-chloropyrazinyl) —Cl
D192 (a, b, c, and d) -2-(3-chloropyrazinyl) —Br
D193 (a, b, c, and d) -2-(3-chloropyrazinyl) —I
D194 (a, b, c, and d) -2-(3-chloropyrazinyl) -n-butyl
D195 (a, b, c, and d) -2-(3-chloropyrazinyl) -n-propyl
D196 (a, b, c, and d) -2-(3-chloropyrazinyl) -iso-propyl
D197 (a, b, c, and d) -2-(3-methylpyrazinyl) -tert-butyl
D198 (a, b, c, and d) -2-(3-methylpyrazinyl) -iso-butyl
D199 (a, b, c, and d) -2-(3-methylpyrazinyl) -sec-butyl
D200 (a, b, c, and d) -2-(3-methylpyrazinyl) -cyclohexyl
D201 (a, b, c, and d) -2-(3-methylpyrazinyl) -tert-butoxy
D202 (a, b, c, and d) -2-(3-methylpyrazinyl) -iso-propoxy
D203 (a, b, c, and d) -2-(3-methylpyrazinyl) —CF3
D204 (a, b, c, and d) -2-(3-methylpyrazinyl) —OCF3
D205 (a, b, c, and d) -2-(3-methylpyrazinyl) —Cl
D206 (a, b, c, and d) -2-(3-methylpyrazinyl) —Br
D207 (a, b, c, and d) -2-(3-methylpyrazinyl) —I
D208 (a, b, c, and d) -2-(3-methylpyrazinyl) -n-butyl
D209 (a, b, c, and d) -2-(3-methylpyrazinyl) -n-propyl
D210 (a, b, c, and d) -2-(3-methylpyrazinyl) -iso-propyl
D211 (a, b, c, and d) -2-(3-fluoropyrazinyl) -tert-butyl
D212 (a, b, c, and d) -2-(3-fluoropyrazinyl) -iso-butyl
D213 (a, b, c, and d) -2-(3-fluoropyrazinyl) -sec-butyl
D214 (a, b, c, and d) -2-(3-fluoropyrazinyl) -cyclohexyl
D215 (a, b, c, and d) -2-(3-fluoropyrazinyl) -tert-butoxy
D216 (a, b, c, and d) -2-(3-fluoropyrazinyl) -iso-propoxy
D217 (a, b, c, and d) -2-(3-fluoropyrazinyl) —CF3
D218 (a, b, c, and d) -2-(3-fluoropyrazinyl) —OCF3
D219 (a, b, c, and d) -2-(3-fluoropyrazinyl) —Cl
D220 (a, b, c, and d) -2-(3-fluoropyrazinyl) —Br
D221 (a, b, c, and d) -2-(3-fluoropyrazinyl) —I
D222 (a, b, c, and d) -2-(3-fluoropyrazinyl) -n-butyl
D223 (a, b, c, and d) -2-(3-fluoropyrazinyl) -n-propyl
D224 (a, b, c, and d) -2-(3-fluoropyrazinyl) -iso-propyl
D225 (a, b, c, and d) -3-(4-chloropyridazinyl) -tert-butyl
D226 (a, b, c, and d) -3-(4-chloropyridazinyl) -iso-butyl
D227 (a, b, c, and d) -3-(4-chloropyridazinyl) -sec-butyl
D228 (a, b, c, and d) -3-(4-chloropyridazinyl) -cyclohexyl
D229 (a, b, c, and d) -3-(4-chloropyridazinyl) -tert-butoxy
D230 (a, b, c, and d) -3-(4-chloropyridazinyl) -iso-propoxy
D231 (a, b, c, and d) -3-(4-chloropyridazinyl) —CF3
D232 (a, b, c, and d) -3-(4-chloropyridazinyl) —OCF3
D233 (a, b, c, and d) -3-(4-chloropyridazinyl) —Cl
D234 (a, b, c, and d) -3-(4-chloropyridazinyl) —Br
D235 (a, b, c, and d) -3-(4-chloropyridazinyl) —I
D236 (a, b, c, and d) -3-(4-chloropyridazinyl) -n-butyl
D237 (a, b, c, and d) -3-(4-chloropyridazinyl) -n-propyl
D238 (a, b, c, and d) -3-(4-chloropyridazinyl) -iso-propyl
D239 (a, b, c, and d) -3-(4-methylpyridazinyl) -tert-butyl
D240 (a, b, c, and d) -3-(4-methylpyridazinyl) -iso-butyl
D241 (a, b, c, and d) -3-(4-methylpyridazinyl) -sec-butyl
D242 (a, b, c, and d) -3-(4-methylpyridazinyl) -cyclohexyl
D243 (a, b, c, and d) -3-(4-methylpyridazinyl) -tert-butoxy
D244 (a, b, c, and d) -3-(4-methylpyridazinyl) -iso-propoxy
D245 (a, b, c, and d) -3-(4-methylpyridazinyl) —CF3
D246 (a, b, c, and d) -3-(4-methylpyridazinyl) —OCF3
D247 (a, b, c, and d) -3-(4-methylpyridazinyl) —Cl
D248 (a, b, c, and d) -3-(4-methylpyridazinyl) —Br
D249 (a, b, c, and d) -3-(4-methylpyridazinyl) —I
D250 (a, b, c, and d) -3-(4-methylpyridazinyl) -n-butyl
D251 (a, b, c, and d) -3-(4-methylpyridazinyl) -n-propyl
D252 (a, b, c, and d) -3-(4-methylpyridazinyl) -iso-propyl
D253 (a, b, c, and d) -3-(4-fluoropyridazinyl) -tert-butyl
D254 (a, b, c, and d) -3-(4-fluoropyridazinyl) -iso-butyl
D255 (a, b, c, and d) -3-(4-fluoropyridazinyl) -sec-butyl
D256 (a, b, c, and d) -3-(4-fluoropyridazinyl) -cyclohexyl
D257 (a, b, c, and d) -3-(4-fluoropyridazinyl) -tert-butoxy
D258 (a, b, c, and d) -3-(4-fluoropyridazinyl) -iso-propoxy
D259 (a, b, c, and d) -3-(4-fluoropyridazinyl) —CF3
D260 (a, b, c, and d) -3-(4-fluoropyridazinyl) —OCF3
D261 (a, b, c, and d) -3-(4-fluoropyridazinyl) —Cl
D262 (a, b, c, and d) -3-(4-fluoropyridazinyl) —Br
D263 (a, b, c, and d) -3-(4-fluoropyridazinyl) —I
D264 (a, b, c, and d) -3-(4-fluoropyridazinyl) -n-butyl
D265 (a, b, c, and d) -3-(4-fluoropyridazinyl) -n-propyl
D266 (a, b, c, and d) -3-(4-fluoropyridazinyl) -iso-propyl
D267 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -tert-butyl
D268 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -iso-butyl
D269 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -sec-butyl
D270 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -cyclohexyl
D271 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -tert-butoxy
D272 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -iso-propoxy
D273 (a, b, c, and d) -5-(4-chlorothiadiazolyl) —CF3
D274 (a, b, c, and d) -5-(4-chlorothiadiazolyl) —OCF3
D275 (a, b, c, and d) -5-(4-chlorothiadiazolyl) —Cl
D276 (a, b, c, and d) -5-(4-chlorothiadiazolyl) —Br
D277 (a, b, c, and d) -5-(4-chlorothiadiazolyl) —I
D278 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -n-butyl
D279 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -n-propyl
D280 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -iso-propyl
D281 (a, b, c, and d) -5-(4-methylthiadiazolyl) -tert-butyl
D282 (a, b, c, and d) -5-(4-methylthiadiazolyl) -iso-butyl
D283 (a, b, c, and d) -5-(4-methylthiadiazolyl) -sec-butyl
D284 (a, b, c, and d) -5-(4-methylthiadiazolyl) -cyclohexyl
D285 (a, b, c, and d) -5-(4-methylthiadiazolyl) -tert-butoxy
D286 (a, b, c, and d) -5-(4-methylthiadiazolyl) -iso-propoxy
D287 (a, b, c, and d) -5-(4-methylthiadiazolyl) —CF3
D288 (a, b, c, and d) -5-(4-methylthiadiazolyl) —OCF3
D289 (a, b, c, and d) -5-(4-methylthiadiazolyl) —Cl
D290 (a, b, c, and d) -5-(4-methylthiadiazolyl) —Br
D291 (a, b, c, and d) -5-(4-methylthiadiazolyl) —I
D292 (a, b, c, and d) -5-(4-methylthiadiazolyl) -n-butyl
D293 (a, b, c, and d) -5-(4-methylthiadiazolyl) -n-propyl
D294 (a, b, c, and d) -5-(4-methylthiadiazolyl) -iso-propyl
D295 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -tert-butyl
D296 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -iso-butyl
D297 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -sec-butyl
D298 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -cyclohexyl
D299 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -tert-butoxy
D300 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -iso-propoxy
D301 (a, b, c, and d) -5-(4-fluorothiadiazolyl) —CF3
D302 (a, b, c, and d) -5-(4-fluorothiadiazolyl) —OCF3
D303 (a, b, c, and d) -5-(4-fluorothiadiazolyl) —Cl
D304 (a, b, c, and d) -5-(4-fluorothiadiazolyl) —Br
D305 (a, b, c, and d) -5-(4-fluorothiadiazolyl) —I
D306 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -n-butyl
D307 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -n-propyl
D308 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -iso-propyl
“a” means R3 is —H.
“b” means R3 is —CH3 and the Nitro(cyano)vinylpiperazine Compound is racemic.
“c” means R3 is —CH3 and the carbon atom to which R3 is attached is in the (R) configuration.
“d” means R3 is —CH3 and the carbon atom to which R3 is attached is in the (S) configuration.

TABLE 5
(VII)
and pharmaceutically acceptable salts thereof, where:
Compound Ar1 R8a
E1 (a, b, c, and d) -2-(3-chloropyridyl) -tert-butyl
E2 (a, b, c, and d) -2-(3-chloropyridyl) -iso-butyl
E3 (a, b, c, and d) -2-(3-chloropyridyl) -sec-butyl
E4 (a, b, c, and d) -2-(3-chloropyridyl) -cyclohexyl
E5 (a, b, c, and d) -2-(3-chloropyridyl) -tert-butoxy
E6 (a, b, c, and d) -2-(3-chloropyridyl) -iso-propoxy
E7 (a, b, c, and d) -2-(3-chloropyridyl) —CF3
E8 (a, b, c, and d) -2-(3-chloropyridyl) —OCF3
E9 (a, b, c, and d) -2-(3-chloropyridyl) —Cl
E10 (a, b, c, and d) -2-(3-chloropyridyl) —Br
E11 (a, b, c, and d) -2-(3-chloropyridyl) —I
E12 (a, b, c, and d) -2-(3-chloropyridyl) -n-butyl
E13 (a, b, c, and d) -2-(3-chloropyridyl) -n-propyl
E14 (a, b, c, and d) -2-(3-chloropyridyl) -iso-propyl
E15 (a, b, c, and d) -2-(3-fluoropyridyl) -tert-butyl
E16 (a, b, c, and d) -2-(3-fluoropyridyl) -iso-butyl
E17 (a, b, c, and d) -2-(3-fluoropyridyl) -sec-butyl
E18 (a, b, c, and d) -2-(3-fluoropyridyl) -cyclohexyl
E19 (a, b, c, and d) -2-(3-fluoropyridyl) -tert-butoxy
E20 (a, b, c, and d) -2-(3-fluoropyridyl) -iso-propoxy
E21 (a, b, c, and d) -2-(3-fluoropyridyl) —CF3
E22 (a, b, c, and d) -2-(3-fluoropyridyl) —OCF3
E23 (a, b, c, and d) -2-(3-fluoropyridyl) —Cl
E24 (a, b, c, and d) -2-(3-fluoropyridyl) —Br
E25 (a, b, c, and d) -2-(3-fluoropyridyl) —I
E26 (a, b, c, and d) -2-(3-fluoropyridyl) -n-butyl
E27 (a, b, c, and d) -2-(3-fluoropyridyl) -n-propyl
E28 (a, b, c, and d) -2-(3-fluoropyridyl) -iso-propyl
E29 (a, b, c, and d) -2-(3-methylpyridyl) -tert-butyl
E30 (a, b, c, and d) -2-(3-methylpyridyl) -iso-butyl
E31 (a, b, c, and d) -2-(3-methylpyridyl) -sec-butyl
E32 (a, b, c, and d) -2-(3-methylpyridyl) -cyclohexyl
E33 (a, b, c, and d) -2-(3-methylpyridyl) -tert-butoxy
E34 (a, b, c, and d) -2-(3-methylpyridyl) -iso-propoxy
E35 (a, b, c, and d) -2-(3-methylpyridyl) —CF3
E36 (a, b, c, and d) -2-(3-methylpyridyl) —OCF3
E37 (a, b, c, and d) -2-(3-methylpyridyl) —Cl
E38 (a, b, c, and d) -2-(3-methylpyridyl) —Br
E39 (a, b, c, and d) -2-(3-methylpyridyl) —I
E40 (a, b, c, and d) -2-(3-methylpyridyl) -n-butyl
E41 (a, b, c, and d) -2-(3-methylpyridyl) -n-propyl
E42 (a, b, c, and d) -2-(3-methylpyridyl) -iso-propyl
E43 (a, b, c, and d) -2-(3-CF3-pyridyl) -tert-butyl
E44 (a, b, c, and d) -2-(3-CF3-pyridyl) -iso-butyl
E45 (a, b, c, and d) -2-(3-CF3-pyridyl) -sec-butyl
E46 (a, b, c, and d) -2-(3-CF3-pyridyl) -cyclohexyl
E47 (a, b, c, and d) -2-(3-CF3-pyridyl) -tert-butoxy
E48 (a, b, c, and d) -2-(3-CF3-pyridyl) -iso-propoxy
E49 (a, b, c, and d) -2-(3-CF3-pyridyl) —CF3
E50 (a, b, c, and d) -2-(3-CF3-pyridyl) —OCF3
E51 (a, b, c, and d) -2-(3-CF3-pyridyl) —Cl
E52 (a, b, c, and d) -2-(3-CF3-pyridyl) —Br
E53 (a, b, c, and d) -2-(3-CF3-pyridyl) —I
E54 (a, b, c, and d) -2-(3-CF3-pyridyl) -n-butyl
E55 (a, b, c, and d) -2-(3-CF3-pyridyl) -n-propyl
E56 (a, b, c, and d) -2-(3-CF3-pyridyl) -iso-propyl
E57 (a, b, c, and d) -2-(3-CHF2-pyridyl) -tert-butyl
E58 (a, b, c, and d) -2-(3-CHF2-pyridyl) -iso-butyl
E59 (a, b, c, and d) -2-(3-CHF2-pyridyl) -sec-butyl
E60 (a, b, c, and d) -2-(3-CHF2-pyridyl) -cyclohexyl
E61 (a, b, c, and d) -2-(3-CHF2-pyridyl) -tert-butoxy
E62 (a, b, c, and d) -2-(3-CHF2-pyridyl) -iso-propoxy
E63 (a, b, c, and d) -2-(3-CHF2-pyridyl) —CF3
E64 (a, b, c, and d) -2-(3-CHF2-pyridyl) —OCF3
E65 (a, b, c, and d) -2-(3-CHF2-pyridyl) —Cl
E66 (a, b, c, and d) -2-(3-CHF2-pyridyl) —Br
E67 (a, b, c, and d) -2-(3-CHF2-pyridyl) —I
E68 (a, b, c, and d) -2-(3-CHF2-pyridyl) -n-butyl
E69 (a, b, c, and d) -2-(3-CHF2-pyridyl) -n-propyl
E70 (a, b, c, and d) -2-(3-CHF2-pyridyl) -iso-propyl
E71 (a, b, c, and d) -2-(3-hydroxypyridyl) -tert-butyl
E72 (a, b, c, and d) -2-(3-hydroxypyridyl) -iso-butyl
E73 (a, b, c, and d) -2-(3-hydroxypyridyl) -sec-butyl
E74 (a, b, c, and d) -2-(3-hydroxypyridyl) -cyclohexyl
E75 (a, b, c, and d) -2-(3-hydroxypyridyl) -tert-butoxy
E76 (a, b, c, and d) -2-(3-hydroxypyridyl) -iso-propoxy
E77 (a, b, c, and d) -2-(3-hydroxypyridyl) —CF3
E78 (a, b, c, and d) -2-(3-hydroxypyridyl) —OCF3
E79 (a, b, c, and d) -2-(3-hydroxypyridyl) —Cl
E80 (a, b, c, and d) -2-(3-hydroxypyridyl) —Br
E81 (a, b, c, and d) -2-(3-hydroxypyridyl) —I
E82 (a, b, c, and d) -2-(3-hydroxypyridyl) -n-butyl
E83 (a, b, c, and d) -2-(3-hydroxypyridyl) -n-propyl
E84 (a, b, c, and d) -2-(3-hydroxypyridyl) -iso-propyl
E85 (a, b, c, and d) -2-(3-nitropyridyl) -tert-butyl
E86 (a, b, c, and d) -2-(3-nitropyridyl) -iso-butyl
E87 (a, b, c, and d) -2-(3-nitropyridyl) -sec-butyl
E88 (a, b, c, and d) -2-(3-nitropyridyl) -cyclohexyl
E89 (a, b, c, and d) -2-(3-nitropyridyl) -tert-butoxy
E90 (a, b, c, and d) -2-(3-nitropyridyl) -iso-propoxy
E91 (a, b, c, and d) -2-(3-nitropyridyl) —CF3
E92 (a, b, c, and d) -2-(3-nitropyridyl) —OCF3
E93 (a, b, c, and d) -2-(3-nitropyridyl) —Cl
E94 (a, b, c, and d) -2-(3-nitropyridyl) —Br
E95 (a, b, c, and d) -2-(3-nitropyridyl) —I
E96 (a, b, c, and d) -2-(3-nitropyridyl) -n-butyl
E97 (a, b, c, and d) -2-(3-nitropyridyl) -n-propyl
E98 (a, b, c, and d) -2-(3-nitropyridyl) -iso-propyl
E99 (a, b, c, and d) -2-(3-cyanopyridyl) -tert-butyl
E100 (a, b, c, and d) -2-(3-cyanopyridyl) -iso-butyl
E101 (a, b, c, and d) -2-(3-cyanopyridyl) -sec-butyl
E102 (a, b, c, and d) -2-(3-cyanopyridyl) -cyclohexyl
E103 (a, b, c, and d) -2-(3-cyanopyridyl) -tert-butoxy
E104 (a, b, c, and d) -2-(3-cyanopyridyl) -iso-propoxy
E105 (a, b, c, and d) -2-(3-cyanopyridyl) —CF3
E106 (a, b, c, and d) -2-(3-cyanopyridyl) —OCF3
E107 (a, b, c, and d) -2-(3-cyanopyridyl) —Cl
E108 (a, b, c, and d) -2-(3-cyanopyridyl) —Br
E109 (a, b, c, and d) -2-(3-cyanopyridyl) —I
E110 (a, b, c, and d) -2-(3-cyanopyridyl) -n-butyl
E111 (a, b, c, and d) -2-(3-cyanopyridyl) -n-propyl
E112 (a, b, c, and d) -2-(3-cyanopyridyl) -isopropyl
E113 (a, b, c, and d) -2-(3-bromopyridyl) -tert-butyl
E114 (a, b, c, and d) -2-(3-bromopyridyl) -iso-butyl
E115 (a, b, c, and d) -2-(3-bromopyridyl) -sec-butyl
E116 (a, b, c, and d) -2-(3-bromopyridyl) -cyclohexyl
E117 (a, b, c, and d) -2-(3-bromopyridyl) -tert-butoxy
E118 (a, b, c, and d) -2-(3-bromopyridyl) -iso-propoxy
E119 (a, b, c, and d) -2-(3-bromopyridyl) —CF3
E120 (a, b, c, and d) -2-(3-bromopyridyl) —OCF3
E121 (a, b, c, and d) -2-(3-bromopyridyl) —Cl
E122 (a, b, c, and d) -2-(3-bromopyridyl) —Br
E123 (a, b, c, and d) -2-(3-bromopyridyl) —I
E124 (a, b, c, and d) -2-(3-bromopyridyl) -n-butyl
E125 (a, b, c, and d) -2-(3-bromopyridyl) -n-propyl
E126 (a, b, c, and d) -2-(3-bromopyridyl) -iso-propyl
E127 (a, b, c, and d) -2-(3-iodopyridyl) -tert-butyl
E128 (a, b, c, and d) -2-(3-iodopyridyl) -iso-butyl
E129 (a, b, c, and d) -2-(3-iodopyridyl) -sec-butyl
E130 (a, b, c, and d) -2-(3-iodopyridyl) -cyclohexyl
E131 (a, b, c, and d) -2-(3-iodopyridyl) -tert-butoxy
E132 (a, b, c, and d) -2-(3-iodopyridyl) -iso-propoxy
E133 (a, b, c, and d) -2-(3-iodopyridyl) —CF3
E134 (a, b, c, and d) -2-(3-iodopyridyl) —OCF3
E135 (a, b, c, and d) -2-(3-iodopyridyl) —Cl
E136 (a, b, c, and d) -2-(3-iodopyridyl) —Br
E137 (a, b, c, and d) -2-(3-iodopyridyl) —I
E138 (a, b, c, and d) -2-(3-iodopyridyl) -n-butyl
E139 (a, b, c, and d) -2-(3-iodopyridyl) -n-propyl
E140 (a, b, c, and d) -2-(3-iodopyridyl) -iso-propyl
E141 (a, b, c, and d) -4-(5-chloropyrimidinyl) -tert-butyl
E142 (a, b, c, and d) -4-(5-chloropyrimidinyl) -iso-butyl
E143 (a, b, c, and d) -4-(5-chloropyrimidinyl) -sec-butyl
E144 (a, b, c, and d) -4-(5-chloropyrimidinyl) -cyclohexyl
E145 (a, b, c, and d) -4-(5-chloropyrimidinyl) -tert-butoxy
E146 (a, b, c, and d) -4-(5-chloropyrimidinyl) -iso-propoxy
E147 (a, b, c, and d) -4-(5-chloropyrimidinyl) —CF3
E148 (a, b, c, and d) -4-(5-chloropyrimidinyl) —OCF3
E149 (a, b, c, and d) -4-(5-chloropyrimidinyl) —Cl
E150 (a, b, c, and d) -4-(5-chloropyrimidinyl) —Br
E151 (a, b, c, and d) -4-(5-chloropyrimidinyl) —I
E152 (a, b, c, and d) -4-(5-chloropyrimidinyl) -n-butyl
E153 (a, b, c, and d) -4-(5-chloropyrimidinyl) -n-propyl
E154 (a, b, c, and d) -4-(5-chloropyrimidinyl) -iso-propyl
E155 (a, b, c, and d) -4-(5-methylpyrimidinyl) -tert-butyl
E156 (a, b, c, and d) -4-(5-methylpyrimidinyl) -iso-butyl
E157 (a, b, c, and d) -4-(5-methylpyrimidinyl) -sec-butyl
E158 (a, b, c, and d) -4-(5-methylpyrimidinyl) -cyclohexyl
E159 (a, b, c, and d) -4-(5-methylpyrimidinyl) -tert-butoxy
E160 (a, b, c, and d) -4-(5-methylpyrimidinyl) -iso-propoxy
E161 (a, b, c, and d) -4-(5-methylpyrimidinyl) —CF3
E162 (a, b, c, and d) -4-(5-methylpyrimidinyl) —OCF3
E163 (a, b, c, and d) -4-(5-methylpyrimidinyl) —Cl
E164 (a, b, c, and d) -4-(5-methylpyrimidinyl) —Br
E165 (a, b, c, and d) -4-(5-methylpyrimidinyl) —I
E166 (a, b, c, and d) -4-(5-methylpyrimidinyl) -n-butyl
E167 (a, b, c, and d) -4-(5-methylpyrimidinyl) -n-propyl
E168 (a, b, c, and d) -4-(5-methylpyrimidinyl) -iso-propyl
E169 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -tert-butyl
E170 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -iso-butyl
E171 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -sec-butyl
E172 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -cyclohexyl
E173 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -tert-butoxy
E174 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -iso-propoxy
E175 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —CF3
E176 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —OCF3
E177 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —Cl
E178 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —Br
E179 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —I
E180 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -n-butyl
E181 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -n-propyl
E182 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -iso-propyl
E183 (a, b, c, and d) -2-(3-chloropyrazinyl) -tert-butyl
E184 (a, b, c, and d) -2-(3-chloropyrazinyl) -iso-butyl
E185 (a, b, c, and d) -2-(3-chloropyrazinyl) -sec-butyl
E186 (a, b, c, and d) -2-(3-chloropyrazinyl) -cyclohexyl
E187 (a, b, c, and d) -2-(3-chloropyrazinyl) -tert-butoxy
E188 (a, b, c, and d) -2-(3-chloropyrazinyl) -iso-propoxy
E189 (a, b, c, and d) -2-(3-chloropyrazinyl) —CF3
E190 (a, b, c, and d) -2-(3-chloropyrazinyl) —OCF3
E191 (a, b, c, and d) -2-(3-chloropyrazinyl) —Cl
E192 (a, b, c, and d) -2-(3-chloropyrazinyl) —Br
E193 (a, b, c, and d) -2-(3-chloropyrazinyl) —I
E194 (a, b, c, and d) -2-(3-chloropyrazinyl) -n-butyl
E195 (a, b, c, and d) -2-(3-chloropyrazinyl) -n-propyl
E196 (a, b, c, and d) -2-(3-chloropyrazinyl) -iso-propyl
E197 (a, b, c, and d) -2-(3-methylpyrazinyl) -tert-butyl
E198 (a, b, c, and d) -2-(3-methylpyrazinyl) -iso-butyl
E199 (a, b, c, and d) -2-(3-methylpyrazinyl) -sec-butyl
E200 (a, b, c, and d) -2-(3-methylpyrazinyl) -cyclohexyl
E201 (a, b, c, and d) -2-(3-methylpyrazinyl) -tert-butoxy
E202 (a, b, c, and d) -2-(3-methylpyrazinyl) -iso-propoxy
E203 (a, b, c, and d) -2-(3-methylpyrazinyl) —CF3
E204 (a, b, c, and d) -2-(3-methylpyrazinyl) —OCF3
E205 (a, b, c, and d) -2-(3-methylpyrazinyl) —Cl
E206 (a, b, c, and d) -2-(3-methylpyrazinyl) —Br
E207 (a, b, c, and d) -2-(3-methylpyrazinyl) —I
E208 (a, b, c, and d) -2-(3-methylpyrazinyl) -n-butyl
E209 (a, b, c, and d) -2-(3-methylpyrazinyl) -n-propyl
E210 (a, b, c, and d) -2-(3-methylpyrazinyl) -iso-propyl
E211 (a, b, c, and d) -2-(3-fluoropyrazinyl) -tert-butyl
E212 (a, b, c, and d) -2-(3-fluoropyrazinyl) -iso-butyl
E213 (a, b, c, and d) -2-(3-fluoropyrazinyl) -sec-butyl
E214 (a, b, c, and d) -2-(3-fluoropyrazinyl) -cyclohexyl
E215 (a, b, c, and d) -2-(3-fluoropyrazinyl) -tert-butoxy
E216 (a, b, c, and d) -2-(3-fluoropyrazinyl) -iso-propoxy
E217 (a, b, c, and d) -2-(3-fluoropyrazinyl) —CF3
E218 (a, b, c, and d) -2-(3-fluoropyrazinyl) —OCF3
E219 (a, b, c, and d) -2-(3-fluoropyrazinyl) —Cl
E220 (a, b, c, and d) -2-(3-fluoropyrazinyl) —Br
E221 (a, b, c, and d) -2-(3-fluoropyrazinyl) —I
E222 (a, b, c, and d) -2-(3-fluoropyrazinyl) -n-butyl
E223 (a, b, c, and d) -2-(3-fluoropyrazinyl) -n-propyl
E224 (a, b, c, and d) -2-(3-fluoropyrazinyl) -iso-propyl
E225 (a, b, c, and d) -3-(4-chloropyridazinyl) -tert-butyl
E226 (a, b, c, and d) -3-(4-chloropyridazinyl) -iso-butyl
E227 (a, b, c, and d) -3-(4-chloropyridazinyl) -sec-butyl
E228 (a, b, c, and d) -3-(4-chloropyridazinyl) -cyclohexyl
E229 (a, b, c, and d) -3-(4-chloropyridazinyl) -tert-butoxy
E230 (a, b, c, and d) -3-(4-chloropyridazinyl) -iso-propoxy
E231 (a, b, c, and d) -3-(4-chloropyridazinyl) —CF3
E232 (a, b, c, and d) -3-(4-chloropyridazinyl) —OCF3
E233 (a, b, c, and d) -3-(4-chloropyridazinyl) —Cl
E234 (a, b, c, and d) -3-(4-chloropyridazinyl) —Br
E235 (a, b, c, and d) -3-(4-chloropyridazinyl) —I
E236 (a, b, c, and d) -3-(4-chloropyridazinyl) -n-butyl
E237 (a, b, c, and d) -3-(4-chloropyridazinyl) -n-propyl
E238 (a, b, c, and d) -3-(4-chloropyridazinyl) -iso-propyl
E239 (a, b, c, and d) -3-(4-methylpyridazinyl) -tert-butyl
E240 (a, b, c, and d) -3-(4-methylpyridazinyl) -iso-butyl
E241 (a, b, c, and d) -3-(4-methylpyridazinyl) -sec-butyl
E242 (a, b, c, and d) -3-(4-methylpyridazinyl) -cyclohexyl
E243 (a, b, c, and d) -3-(4-methylpyridazinyl) -tert-butoxy
E244 (a, b, c, and d) -3-(4-methylpyridazinyl) -iso-propoxy
E245 (a, b, c, and d) -3-(4-methylpyridazinyl) —CF3
E246 (a, b, c, and d) -3-(4-methylpyridazinyl) —OCF3
E247 (a, b, c, and d) -3-(4-methylpyridazinyl) —Cl
E248 (a, b, c, and d) -3-(4-methylpyridazinyl) —Br
E249 (a, b, c, and d) -3-(4-methylpyridazinyl) —I
E250 (a, b, c, and d) -3-(4-methylpyridazinyl) -n-butyl
E251 (a, b, c, and d) -3-(4-methylpyridazinyl) -n-propyl
E252 (a, b, c, and d) -3-(4-methylpyridazinyl) -iso-propyl
E253 (a, b, c, and d) -3-(4-fluoropyridazinyl) -tert-butyl
E254 (a, b, c, and d) -3-(4-fluoropyridazinyl) -iso-butyl
E255 (a, b, c, and d) -3-(4-fluoropyridazinyl) -sec-butyl
E256 (a, b, c, and d) -3-(4-fluoropyridazinyl) -cyclohexyl
E257 (a, b, c, and d) -3-(4-fluoropyridazinyl) -tert-butoxy
E258 (a, b, c, and d) -3-(4-fluoropyridazinyl) -iso-propoxy
E259 (a, b, c, and d) -3-(4-fluoropyridazinyl) —CF3
E260 (a, b, c, and d) -3-(4-fluoropyridazinyl) —OCF3
E261 (a, b, c, and d) -3-(4-fluoropyridazinyl) —Cl
E262 (a, b, c, and d) -3-(4-fluoropyridazinyl) —Br
E263 (a, b, c, and d) -3-(4-fluoropyridazinyl) —I
E264 (a, b, c, and d) -3-(4-fluoropyridazinyl) -n-butyl
E265 (a, b, c, and d) -3-(4-fluoropyridazinyl) -n-propyl
E266 (a, b, c, and d) -3-(4-fluoropyridazinyl) -iso-propyl
E267 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -tert-butyl
E268 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -iso-butyl
E269 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -sec-butyl
E270 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -cyclohexyl
E271 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -tert-butoxy
E272 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -iso-propoxy
E273 (a, b, c, and d) -5-(4-chlorothiadiazolyl) —CF3
E274 (a, b, c, and d) -5-(4-chlorothiadiazolyl) —OCF3
E275 (a, b, c, and d) -5-(4-chlorothiadiazolyl) —Cl
E276 (a, b, c, and d) -5-(4-chlorothiadiazolyl) —Br
E277 (a, b, c, and d) -5-(4-chlorothiadiazolyl) —I
E278 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -n-butyl
E279 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -n-propyl
E280 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -iso-propyl
E281 (a, b, c, and d) -5-(4-methylthiadiazolyl) -tert-butyl
E282 (a, b, c, and d) -5-(4-methylthiadiazolyl) -iso-butyl
E283 (a, b, c, and d) -5-(4-methylthiadiazolyl) -sec-butyl
E284 (a, b, c, and d) -5-(4-methylthiadiazolyl) -cyclohexyl
E285 (a, b, c, and d) -5-(4-methylthiadiazolyl) -tert-butoxy
E286 (a, b, c, and d) -5-(4-methylthiadiazolyl) -iso-propoxy
E287 (a, b, c, and d) -5-(4-methylthiadiazolyl) —CF3
E288 (a, b, c, and d) -5-(4-methylthiadiazolyl) —OCF3
E289 (a, b, c, and d) -5-(4-methylthiadiazolyl) —Cl
E290 (a, b, c, and d) -5-(4-methylthiadiazolyl) —Br
E291 (a, b, c, and d) -5-(4-methylthiadiazolyl) —I
E292 (a, b, c, and d) -5-(4-methylthiadiazolyl) -n-butyl
E293 (a, b, c, and d) -5-(4-methylthiadiazolyl) -n-propyl
E294 (a, b, c, and d) -5-(4-methylthiadiazolyl) -iso-propyl
E295 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -tert-butyl
E296 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -iso-butyl
E297 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -sec-butyl
E298 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -cyclohexyl
E299 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -tert-butoxy
E300 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -iso-propoxy
E301 (a, b, c, and d) -5-(4-fluorothiadiazolyl) —CF3
E302 (a, b, c, and d) -5-(4-fluorothiadiazolyl) —OCF3
E303 (a, b, c, and d) -5-(4-fluorothiadiazolyl) —Cl
E304 (a, b, c, and d) -5-(4-fluorothiadiazolyl) —Br
E305 (a, b, c, and d) -5-(4-fluorothiadiazolyl) —I
E306 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -n-butyl
E307 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -n-propyl
E308 (a, b, c, and d) -5-(4-fluorothiadiazolyl) -iso-propyl
“a” means R3 is —H.
“b” means R3 is —CH3 and the Nitro(cyano)vinylpiperazine Compound is racemic.
“c” means R3 is —CH3 and the carbon atom to which R3 is attached is in the (R) configuration.
“d” means R3 is —CH3 and the carbon atom to which R3 is attached is in the (S) configuration.

TABLE 6
(VIII)
and pharmaceutically acceptable salts thereof, where:
Compound Ar1 R8a
F1(a, b, c, and d) -2-(3-chloropyridyl) -tert-butyl
F2 (a, b, c, and d) -2-(3-chloropyridyl) -iso-butyl
F3 (a, b, c, and d) -2-(3-chloropyridyl) -sec-butyl
F4 (a, b, c, and d) -2-(3-chloropyridyl) -cyclohexyl
F5 (a, b, c, and d) -2-(3-chloropyridyl) -tert-butoxy
F6 (a, b, c, and d) -2-(3-chloropyridyl) -iso-propoxy
F7 (a, b, c, and d) -2-(3-chloropyridyl) —CF3
F8 (a, b, c, and d) -2-(3-chloropyridyl) —OCF3
F9 (a, b, c, and d) -2-(3-chloropyridyl) —Cl
F10 (a, b, c, and d) -2-(3-chloropyridyl) —Br
F11 (a, b, c, and d) -2-(3-chloropyridyl) —I
F12 (a, b, c, and d) -2-(3-chloropyridyl) -n-butyl
F13 (a, b, c, and d) -2-(3-chloropyridyl) -n-propyl
F14 (a, b, c, and d) -2-(3-chloropyridyl) -iso-propyl
F15 (a, b, c, and d) -2-(3-fluoropyridyl) -tert-butyl
F16 (a, b, c, and d) -2-(3-fluoropyridyl) -iso-butyl
F17 (a, b, c, and d) -2-(3-fluoropyridyl) -sec-butyl
F18 (a, b, c, and d) -2-(3-fluoropyridyl) -cyclohexyl
F19 (a, b, c, and d) -2-(3-fluoropyridyl) -tert-butoxy
F20 (a, b, c, and d) -2-(3-fluoropyridyl) -iso-propoxy
F21 (a, b, c, and d) -2-(3-fluoropyridyl) —CF3
F22 (a, b, c, and d) -2-(3-fluoropyridyl) —OCF3
F23 (a, b, c, and d) -2-(3-fluoropyridyl) —Cl
F24 (a, b, c, and d) -2-(3-fluoropyridyl) —Br
F25 (a, b, c, and d) -2-(3-fluoropyridyl) —I
F26 (a, b, c, and d) -2-(3-fluoropyridyl) -n-butyl
F27 (a, b, c, and d) -2-(3-fluoropyridyl) -n-propyl
F28 (a, b, c, and d) -2-(3-fluoropyridyl) -iso-propyl
F29 (a, b, c, and d) -2-(3-methylpyridyl) -tert-butyl
F30 (a, b, c, and d) -2-(3-methylpyridyl) -iso-butyl
F31 (a, b, c, and d) -2-(3-methylpyridyl) -sec-butyl
F32 (a, b, c, and d) -2-(3-methylpyridyl) -cyclohexyl
F33 (a, b, c, and d) -2-(3-methylpyridyl) -tert-butoxy
F34 (a, b, c, and d) -2-(3-methylpyridyl) -iso-propoxy
F35 (a, b, c, and d) -2-(3-methylpyridyl) —CF3
F36 (a, b, c, and d) -2-(3-methylpyridyl) —OCF3
F37 (a, b, c, and d) -2-(3-methylpyridyl) —Cl
F38 (a, b, c, and d) -2-(3-methylpyridyl) —Br
F39 (a, b, c, and d) -2-(3-methylpyridyl) —I
F40 (a, b, c, and d) -2-(3-methylpyridyl) -n-butyl
F41 (a, b, c, and d) -2-(3-methylpyridyl) -n-propyl
F42 (a, b, c, and d) -2-(3-methylpyridyl) -iso-propyl
F43 (a, b, c, and d) -2-(3-CF3-pyridyl) -tert-butyl
F44 (a, b, c, and d) -2-(3-CF3-pyridyl) -iso-butyl
F45 (a, b, c, and d) -2-(3-CF3-pyridyl) -sec-butyl
F46 (a, b, c, and d) -2-(3-CF3-pyridyl) -cyclohexyl
F47 (a, b, c, and d) -2-(3-CF3-pyridyl) -tert-butoxy
F48 (a, b, c, and d) -2-(3-CF3-pyridyl) -iso-propoxy
F49 (a, b, c, and d) -2-(3-CF3-pyridyl) —CF3
F50 (a, b, c, and d) -2-(3-CF3-pyridyl) —OCF3
F51 (a, b, c, and d) -2-(3-CF3-pyridyl) —Cl
F52 (a, b, c, and d) -2-(3-CF3-pyridyl) —Br
F53 (a, b, c, and d) -2-(3-CF3-pyridyl) —I
F54 (a, b, c, and d) -2-(3-CF3-pyridyl) -n-butyl
F55 (a, b, c, and d) -2-(3-CF3-pyridyl) -n-propyl
F56 (a, b, c, and d) -2-(3-CF3-pyridyl) -iso-propyl
F57 (a, b, c, and d) -2-(3-CHF2-pyridyl) -tert-butyl
F58 (a, b, c, and d) -2-(3-CHF2-pyridyl) -iso-butyl
F59 (a, b, c, and d) -2-(3-CHF2-pyridyl) -sec-butyl
F60 (a, b, c, and d) -2-(3-CHF2-pyridyl) -cyclohexyl
F61 (a, b, c, and d) -2-(3-CHF2-pyridyl) -tert-butoxy
F62 (a, b, c, and d) -2-(3-CHF2-pyridyl) -iso-propoxy
F63 (a, b, c, and d) -2-(3-CHF2-pyridyl) —CF3
F64 (a, b, c, and d) -2-(3-CHF2-pyridyl) —OCF3
F65 (a, b, c, and d) -2-(3-CHF2-pyridyl) —Cl
F66 (a, b, c, and d) -2-(3-CHF2-pyridyl) —Br
F67 (a, b, c, and d) -2-(3-CHF2-pyridyl) —I
F68 (a, b, c, and d) -2-(3-CHF2-pyridyl) -n-butyl
F69 (a, b, c, and d) -2-(3-CHF2-pyridyl) -n-propyl
F70 (a, b, c, and d) -2-(3-CHF2-pyridyl) -iso-propyl
F71 (a, b, c, and d) -2-(3-hydroxypyridyl) -tert-butyl
F72 (a, b, c, and d) -2-(3-hydroxypyridyl) -iso-butyl
F73 (a, b, c, and d) -2-(3-hydroxypyridyl) -sec-butyl
F74 (a, b, c, and d) -2-(3-hydroxypyridyl) -cyclohexyl
F75 (a, b, c, and d) -2-(3-hydroxypyridyl) -tert-butoxy
F76 (a, b, c, and d) -2-(3-hydroxypyridyl) -iso-propoxy
F77 (a, b, c, and d) -2-(3-hydroxypyridyl) —CF3
F78 (a, b, c, and d) -2-(3-hydroxypyridyl) —OCF3
F79 (a, b, c, and d) -2-(3-hydroxypyridyl) —Cl
F80 (a, b, c, and d) -2-(3-hydroxypyridyl) —Br
F81 (a, b, c, and d) -2-(3-hydroxypyridyl) —I
F82 (a, b, c, and d) -2-(3-hydroxypyridyl) -n-butyl
F83 (a, b, c, and d) -2-(3-hydroxypyridyl) -n-propyl
F84 (a, b, c, and d) -2-(3-hydroxypyridyl) -iso-propyl
F85 (a, b, c, and d) -2-(3-nitropyridyl) -tert-butyl
F86 (a, b, c, and d) -2-(3-nitropyridyl) -iso-butyl
F87 (a, b, c, and d) -2-(3-nitropyridyl) -sec-butyl
F88 (a, b, c, and d) -2-(3-nitropyridyl) -cyclohexyl
F89 (a, b, c, and d) -2-(3-nitropyridyl) -tert-butoxy
F90 (a, b, c, and d) -2-(3-nitropyridyl) -iso-propoxy
F91 (a, b, c, and d) -2-(3-nitropyridyl) —CF3
F92 (a, b, c, and d) -2-(3-nitropyridyl) —OCF3
F93 (a, b, c, and d) -2-(3-nitropyridyl) —Cl
F94 (a, b, c, and d) -2-(3-nitropyridyl) —Br
F95 (a, b, c, and d) -2-(3-nitropyridyl) —I
F96 (a, b, c, and d) -2-(3-nitropyridyl) -n-butyl
F97 (a, b, c, and d) -2-(3-nitropyridyl) -n-propyl
F98 (a, b, c, and d) -2-(3-nitropyridyl) -iso-propyl
F99 (a, b, c, and d) -2-(3-cyanopyridyl) -tert-butyl
F100 (a, b, c, and d) -2-(3-cyanopyridyl) -iso-butyl
F101 (a, b, c, and d) -2-(3-cyanopyridyl) -sec-butyl
F102 (a, b, c, and d) -2-(3-cyanopyridyl) -cyclohexyl
F103 (a, b, c, and d) -2-(3-cyanopyridyl) -tert-butoxy
F104 (a, b, c, and d) -2-(3-cyanopyridyl) -iso-propoxy
F105 (a, b, c, and d) -2-(3-cyanopyridyl) —CF3
F106 (a, b, c, and d) -2-(3-cyanopyridyl) —OCF3
F107 (a, b, c, and d) -2-(3-cyanopyridyl) —Cl
F108 (a, b, c, and d) -2-(3-cyanopyridyl) —Br
F109 (a, b, c, and d) -2-(3-cyanopyridyl) —I
F110 (a, b, c, and d) -2-(3-cyanopyridyl) -n-butyl
F111 (a, b, c, and d) -2-(3-cyanopyridyl) -n-propyl
F112 (a, b, c, and d) -2-(3-cyanopyridyl) -isopropyl
F113 (a, b, c, and d) -2-(3-bromopyridyl) -tert-butyl
F114 (a, b, c, and d) -2-(3-bromopyridyl) -iso-butyl
F115 (a, b, c, and d) -2-(3-bromopyridyl) -sec-butyl
F116 (a, b, c, and d) -2-(3-bromopyridyl) -cyclohexyl
F117 (a, b, c, and d) -2-(3-bromopyridyl) -tert-butoxy
F118 (a, b, c, and d) -2-(3-bromopyridyl) -iso-propoxy
F119 (a, b, c, and d) -2-(3-bromopyridyl) —CF3
F120 (a, b, c, and d) -2-(3-bromopyridyl) —OCF3
F121 (a, b, c, and d) -2-(3-bromopyridyl) —Cl
F122 (a, b, c, and d) -2-(3-bromopyridyl) —Br
F123 (a, b, c, and d) -2-(3-bromopyridyl) —I
F124 (a, b, c, and d) -2-(3-bromopyridyl) -n-butyl
F125 (a, b, c, and d) -2-(3-bromopyridyl) -n-propyl
F126 (a, b, c, and d) -2-(3-bromopyridyl) -iso-propyl
F127 (a, b, c, and d) -2-(3-iodopyridyl) -tert-butyl
F128 (a, b, c, and d) -2-(3-iodopyridyl) -iso-butyl
F129 (a, b, c, and d) -2-(3-iodopyridyl) -sec-butyl
F130 (a, b, c, and d) -2-(3-iodopyridyl) -cyclohexyl
F131 (a, b, c, and d) -2-(3-iodopyridyl) -tert-butoxy
F132 (a, b, c, and d) -2-(3-iodopyridyl) -iso-propoxy
F133 (a, b, c, and d) -2-(3-iodopyridyl) —CF3
F134 (a, b, c, and d) -2-(3-iodopyridyl) —OCF3
F135 (a, b, c, and d) -2-(3-iodopyridyl) —Cl
F136 (a, b, c, and d) -2-(3-iodopyridyl) —Br
F137 (a, b, c, and d) -2-(3-iodopyridyl) —I
F138 (a, b, c, and d) -2-(3-iodopyridyl) -n-butyl
F139 (a, b, c, and d) -2-(3-iodopyridyl) -n-propyl
F140 (a, b, c, and d) -2-(3-iodopyridyl) -iso-propyl
F141 (a, b, c, and d) -4-(5-chloropyrimidinyl) -tert-butyl
F142 (a, b, c, and d) -4-(5-chloropyrimidinyl) -iso-butyl
F143 (a, b, c, and d) -4-(5-chloropyrimidinyl) -sec-butyl
F144 (a, b, c, and d) -4-(5-chloropyrimidinyl) -cyclohexyl
F145 (a, b, c, and d) -4-(5-chloropyrimidinyl) -tert-butoxy
F146 (a, b, c, and d) -4-(5-chloropyrimidinyl) -iso-propoxy
F147 (a, b, c, and d) -4-(5-chloropyrimidinyl) —CF3
F148 (a, b, c, and d) -4-(5-chloropyrimidinyl) —OCF3
F149 (a, b, c, and d) -4-(5-chloropyrimidinyl) —Cl
F150 (a, b, c, and d) -4-(5-chloropyrimidinyl) —Br
F151 (a, b, c, and d) -4-(5-chloropyrimidinyl) —I
F152 (a, b, c, and d) -4-(5-chloropyrimidinyl) -n-butyl
F153 (a, b, c, and d) -4-(5-chloropyrimidinyl) -n-propyl
F154 (a, b, c, and d) -4-(5-chloropyrimidinyl) -iso-propyl
F155 (a, b, c, and d) -4-(5-methylpyrimidinyl) -tert-butyl
F156 (a, b, c, and d) -4-(5-methylpyrimidinyl) -iso-butyl
F157 (a, b, c, and d) -4-(5-methylpyrimidinyl) -sec-butyl
F158 (a, b, c, and d) -4-(5-methylpyrimidinyl) -cyclohexyl
F159 (a, b, c, and d) -4-(5-methylpyrimidinyl) -tert-butoxy
F160 (a, b, c, and d) -4-(5-methylpyrimidinyl) -iso-propoxy
F161 (a, b, c, and d) -4-(5-methylpyrimidinyl) —CF3
F162 (a, b, c, and d) -4-(5-methylpyrimidinyl) —OCF3
F163 (a, b, c, and d) -4-(5-methylpyrimidinyl) —Cl
F164 (a, b, c, and d) -4-(5-methylpyrimidinyl) —Br
F165 (a, b, c, and d) -4-(5-methylpyrimidinyl) —I
F166 (a, b, c, and d) -4-(5-methylpyrimidinyl) -n-butyl
F167 (a, b, c, and d) -4-(5-methylpyrimidinyl) -n-propyl
F168 (a, b, c, and d) -4-(5-methylpyrimidinyl) -iso-propyl
F169 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -tert-butyl
F170 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -iso-butyl
F171 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -sec-butyl
F172 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -cyclohexyl
F173 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -tert-butoxy
F174 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -iso-propoxy
F175 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —CF3
F176 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —OCF3
F177 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —Cl
F178 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —Br
F179 (a, b, c, and d) -4-(5-fluoropyrimidinyl) —I
F180 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -n-butyl
F181 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -n-propyl
F182 (a, b, c, and d) -4-(5-fluoropyrimidinyl) -iso-propyl
F183 (a, b, c, and d) -2-(3-chloropyrazinyl) -tert-butyl
F184 (a, b, c, and d) -2-(3-chloropyrazinyl) -iso-butyl
F185 (a, b, c, and d) -2-(3-chloropyrazinyl) -sec-butyl
F186 (a, b, c, and d) -2-(3-chloropyrazinyl) -cyclohexyl
F187 (a, b, c, and d) -2-(3-chloropyrazinyl) -tert-butoxy
F188 (a, b, c, and d) -2-(3-chloropyrazinyl) -iso-propoxy
F189 (a, b, c, and d) -2-(3-chloropyrazinyl) —CF3
F190 (a, b, c, and d) -2-(3-chloropyrazinyl) —OCF3
F191 (a, b, c, and d) -2-(3-chloropyrazinyl) —Cl
F192 (a, b, c, and d) -2-(3-chloropyrazinyl) —Br
F193 (a, b, c, and d) -2-(3-chloropyrazinyl) —I
F194 (a, b, c, and d) -2-(3-chloropyrazinyl) -n-butyl
F195 (a, b, c, and d) -2-(3-chloropyrazinyl) -n-propyl
F196 (a, b, c, and d) -2-(3-chloropyrazinyl) -iso-propyl
F197 (a, b, c, and d) -2-(3-methylpyrazinyl) -tert-butyl
F198 (a, b, c, and d) -2-(3-methylpyrazinyl) -iso-butyl
F199 (a, b, c, and d) -2-(3-methylpyrazinyl) -sec-butyl
F200 (a, b, c, and d) -2-(3-methylpyrazinyl) -cyclohexyl
F201 (a, b, c, and d) -2-(3-methylpyrazinyl) -tert-butoxy
F202 (a, b, c, and d) -2-(3-methylpyrazinyl) -iso-propoxy
F203 (a, b, c, and d) -2-(3-methylpyrazinyl) —CF3
F204 (a, b, c, and d) -2-(3-methylpyrazinyl) —OCF3
F205 (a, b, c, and d) -2-(3-methylpyrazinyl) —Cl
F206 (a, b, c, and d) -2-(3-methylpyrazinyl) —Br
F207 (a, b, c, and d) -2-(3-methylpyrazinyl) —I
F208 (a, b, c, and d) -2-(3-methylpyrazinyl) -n-butyl
F209 (a, b, c, and d) -2-(3-methylpyrazinyl) -n-propyl
F210 (a, b, c, and d) -2-(3-methylpyrazinyl) -iso-propyl
F211 (a, b, c, and d) -2-(3-fluoropyrazinyl) -tert-butyl
F212 (a, b, c, and d) -2-(3-fluoropyrazinyl) -iso-butyl
F213 (a, b, c, and d) -2-(3-fluoropyrazinyl) -sec-butyl
F214 (a, b, c, and d) -2-(3-fluoropyrazinyl) -cyclohexyl
F215 (a, b, c, and d) -2-(3-fluoropyrazinyl) -tert-butoxy
F216 (a, b, c, and d) -2-(3-fluoropyrazinyl) -iso-propoxy
F217 (a, b, c, and d) -2-(3-fluoropyrazinyl) —CF3
F218 (a, b, c, and d) -2-(3-fluoropyrazinyl) —OCF3
F219 (a, b, c, and d) -2-(3-fluoropyrazinyl) —Cl
F220 (a, b, c, and d) -2-(3-fluoropyrazinyl) —Br
F221 (a, b, c, and d) -2-(3-fluoropyrazinyl) —I
F222 (a, b, c, and d) -2-(3-fluoropyrazinyl) -n-butyl
F223 (a, b, c, and d) -2-(3-fluoropyrazinyl) -n-propyl
F224 (a, b, c, and d) -2-(3-fluoropyrazinyl) -iso-propyl
F225 (a, b, c, and d) -3-(4-chloropyridazinyl) -tert-butyl
F226 (a, b, c, and d) -3-(4-chloropyridazinyl) -iso-butyl
F227 (a, b, c, and d) -3-(4-chloropyridazinyl) -sec-butyl
F228 (a, b, c, and d) -3-(4-chloropyridazinyl) -cyclohexyl
F229 (a, b, c, and d) -3-(4-chloropyridazinyl) -tert-butoxy
F230 (a, b, c, and d) -3-(4-chloropyridazinyl) -iso-propoxy
F231 (a, b, c, and d) -3-(4-chloropyridazinyl) —CF3
F232 (a, b, c, and d) -3-(4-chloropyridazinyl) —OCF3
F233 (a, b, c, and d) -3-(4-chloropyridazinyl) —Cl
F234 (a, b, c, and d) -3-(4-chloropyridazinyl) —Br
F235 (a, b, c, and d) -3-(4-chloropyridazinyl) —I
F236 (a, b, c, and d) -3-(4-chloropyridazinyl) -n-butyl
F237 (a, b, c, and d) -3-(4-chloropyridazinyl) -n-propyl
F238 (a, b, c, and d) -3-(4-chloropyridazinyl) -iso-propyl
F239 (a, b, c, and d) -3-(4-methylpyridazinyl) -tert-butyl
F240 (a, b, c, and d) -3-(4-methylpyridazinyl) -iso-butyl
F241 (a, b, c, and d) -3-(4-methylpyridazinyl) -sec-butyl
F242 (a, b, c, and d) -3-(4-methylpyridazinyl) -cyclohexyl
F243 (a, b, c, and d) -3-(4-methylpyridazinyl) -tert-butoxy
F244 (a, b, c, and d) -3-(4-methylpyridazinyl) -iso-propoxy
F245 (a, b, c, and d) -3-(4-methylpyridazinyl) —CF3
F246 (a, b, c, and d) -3-(4-methylpyridazinyl) —OCF3
F247 (a, b, c, and d) -3-(4-methylpyridazinyl) —Cl
F248 (a, b, c, and d) -3-(4-methylpyridazinyl) —Br
F249 (a, b, c, and d) -3-(4-methylpyridazinyl) —I
F250 (a, b, c, and d) -3-(4-methylpyridazinyl) -n-butyl
F251 (a, b, c, and d) -3-(4-methylpyridazinyl) -n-propyl
F252 (a, b, c, and d) -3-(4-methylpyridazinyl) -iso-propyl
F253 (a, b, c, and d) -3-(4-fluoropyridazinyl) -tert-butyl
F254 (a, b, c, and d) -3-(4-fluoropyridazinyl) -iso-butyl
F255 (a, b, c, and d) -3-(4-fluoropyridazinyl) -sec-butyl
F256 (a, b, c, and d) -3-(4-fluoropyridazinyl) -cyclohexyl
F257 (a, b, c, and d) -3-(4-fluoropyridazinyl) -tert-butoxy
F258 (a, b, c, and d) -3-(4-fluoropyridazinyl) -iso-propoxy
F259 (a, b, c, and d) -3-(4-fluoropyridazinyl) —CF3
F260 (a, b, c, and d) -3-(4-fluoropyridazinyl) —OCF3
F261 (a, b, c, and d) -3-(4-fluoropyridazinyl) —Cl
F262 (a, b, c, and d) -3-(4-fluoropyridazinyl) —Br
F263 (a, b, c, and d) -3-(4-fluoropyridazinyl) —I
F264 (a, b, c, and d) -3-(4-fluoropyridazinyl) -n-butyl
F265 (a, b, c, and d) -3-(4-fluoropyridazinyl) -n-propyl
F266 (a, b, c, and d) -3-(4-fluoropyridazinyl) -iso-propyl
F267 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -tert-butyl
F268 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -iso-butyl
F269 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -sec-butyl
F270 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -cyclohexyl
F271 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -tert-butoxy
F272 (a, b, c, and d) -5-(4-chlorothiadiazolyl) -iso-propoxy
F273 (a, b, c, and d) -5-(4-chlorothiadiazolyl) —CF3